379231-04-6OUKYUETWWIPKQR-UHFFFAOYSA-NOUKYUETWWIPKQR-UHFFFAOYSA-N
SaracatinibDTXSID9019135562996-74-1HKSZLNNOFSGOKW-HMWZOHBLSA-NHKSZLNNOFSGOKW-GKHVWRADSA-N
StaurosporineStaurosporin
9,13-Epoxy-1H,9H-diindolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-j][1,7]benzodiazonin-1-one, 2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-11-(methylamino)-, (9S,10R,11R,13R)-
(+)-Staurosporine
9,13-Epoxy-1H,9H-diindolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-j][1,7]benzodiazonin-1-one, 2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-11-(methylamino)-, [9S-(9α,10β,11β,13α)]-
Alkaloid AM-2282 from Streptomyces
Antibiotic 230
Antibiotic AM 2282
DTXSID604113151-28-5UFBJCMHMOXMLKC-UHFFFAOYSA-NUFBJCMHMOXMLKC-UHFFFAOYSA-N
2,4-DinitrophenolDNP
1,3-Dinitro-4-hydroxybenzene
1-Hydroxy-2,4-dinitrobenzene
2,4-dinitrofenol
Aldifen
Dinitrophenol
DINITROPHENOL, 2,4-
Dinofan
Fenoxyl Carbon N
NSC 1532
Phenol, α-dinitro-
UN 1320
UN 1599
α-Dinitrophenol
Phenol, 2,4-dinitro-
DTXSID002052387-86-5IZUPBVBPLAPZRR-UHFFFAOYSA-NIZUPBVBPLAPZRR-UHFFFAOYSA-N
PentachlorophenolPCP
Phenol, pentachloro-
1-Hydroxy-2,3,4,5,6-pentachlorobenzene
1-Hydroxypentachlorobenzene
Chlorophenasic acid
CHLOROPHENATE
Dowicide EC 7
Dura Treet II
Fungifen
Grundier Arbezol
Lauxtol
Liroprem
NSC 263497
Penchlorol
Pentachlorphenol
Perchlorophenol
Permasan
Phenol, 2,3,4,5,6-pentachloro-
Pole topper
Pole topper fluid
Preventol P
Santophen 20
Satophen
UN 3155
Witophen P
Woodtreat A
2,3,4,5,6-Pentachlorophenol
DTXSID70211063380-34-5XEFQLINVKFYRCS-UHFFFAOYSA-NXEFQLINVKFYRCS-UHFFFAOYSA-N
Triclosan5-Chloro-2-(2,4-dichlorophenoxy)phenol
Phenol, 5-chloro-2-(2,4-dichlorophenoxy)-
2, 4, 4'-Trichloro-2'-hydroxydiphenylether
2,2'-Oxybis(1',5'-dichlorophenyl-5-chlorophenol)
2,4,4'-TRICHLORO-2'-HYDROXY DIPHENYLETHER
2',4',4-Trichloro-2-hydroxydiphenyl ether
2',4,4'-Trichloro-2-hydroxydiphenyl ether
2,4,4'-Trichloro-2'-hydroxydiphenyl ether
2'-Hydroxy-2,4,4'-trichlorodiphenyl ether
2-Hydroxy-2',4,4'-trichlorodiphenyl ether
3-Chloro-6-(2,4-dichlorophenoxy)phenol
4-Chloro-2-hydroxyphenyl 2,4-dichlorophenyl ether
5-Chloro-2-(2', 4'-dichlorophenoxy) phenol
Aquasept
Bacti-Stat soap
Cansan TCH
DIPHENYL ETHER, 2,4,4'-TRICHLORO-2'-HYDROXY-
Irgacare MP
Irgacide LP 10
Irgaguard B 1000
Irgaguard B 1325
Irgasan
Irgasan CH 3565
Irgasan DP 30
Irgasan DP 300
Irgasan DP 3000
Irgasan DP 400
Irgasan PE 30
Irgasan PG 60
Microban Additive B
Microban B
Oletron
Phenol, 5-chloro-2-(2,4-dichlorophenoxy)
Phenol, 5-chloro-2-(2,4-dichlorophenoxy)-, dihydrogen phosphate
Sanitized XTX
Sapoderm
SterZac
Tinosan AM 100
Tinosan AM 110
TRICLOSAM
Ultra Fresh NM 100
Ultrafresh NM-V 2
Vinyzene DP 7000
Yujiexin
Zilesan UW
DTXSID5032498518-82-1RHMXXJGYXNZAPX-UHFFFAOYSA-NRHMXXJGYXNZAPX-UHFFFAOYSA-N
Emodin9,10-Anthracenedione, 1,3,8-trihydroxy-6-methyl-
1,3,8-trihidroxi-6-metilantraquinona
1,3,8-Trihydroxy-6-methyl-9,10-anthraquinone
1,3,8-Trihydroxy-6-methylanthrachinon
1,3,8-trihydroxy-6-methylanthraquinone
1,6,8-Trihydroxy-3-methylanthraquinone
3-Methyl-1,6,8-trihydroxyanthraquinone
4,5,7-Trihydroxy-2-methylanthraquinone
Anthraquinone, 1,3,8-trihydroxy-6-methyl-
Frangula emodin
Frangulic acid
NSC 408120
NSC 622947
Rheum emodin
Schuttgelb
DTXSID502523110537-47-0MZOPWQKISXCCTP-UHFFFAOYSA-NMZOPWQKISXCCTP-UHFFFAOYSA-N
MalonobenDTXSID104210664-17-5LFQSCWFLJHTTHZ-UHFFFAOYSA-NLFQSCWFLJHTTHZ-UHFFFAOYSA-N
EthanolEthyl alcohol
AETHANOL
Alcare Hand Degermer
Alcohol
Alcohol anhydrous
Algrain
Anhydrol
Anhydrol PM 4085
Denatured alcohol
Denatured ethanol
Denatured ethyl alcohol
Desinfektol EL
Duplicating Fluid 100C.NPA
Esumiru WK 88
Ethicap
Ethyl hydrate
Ethyl hydroxide
Hinetoless
Infinity Pure
Jaysol S
Methylcarbinol
Molasses alcohol
NSC 85228
Potato alcohol
Sekundasprit
Sterillium Rub
SY Fresh M
Synasol
Tecsol C
UN 1170
UN1170
Vinic alcohol
EtOH
DTXSID902058451-52-5KNAHARQHSZJURB-UHFFFAOYSA-NKNAHARQHSZJURB-UHFFFAOYSA-N
6-Propyl-2-thiouracil6-Propyl-2 thiouracil (PTU)
4(1H)-Pyrimidinone, 2,3-dihydro-6-propyl-2-thioxo-
2,3-Dihydro-6-propyl-2-thioxo-4(1H)-pyrimidinone
2-Mercapto-4-hydroxy-6-n-propylpyrimidine
2-Mercapto-4-hydroxy-6-propylpyrimidine
2-Mercapto-6-propylpyrimidin-4-ol
2-Thio-4-oxo-6-propyl-1,3-pyrimidine
2-Thio-6-propyl-1,3-pyrimidin-4-one
6-n-Propyl-2-thiouracil
6-n-Propylthiouracil
6-Propyl-2-thio-2,4(1H,3H)pyrimidinedione
6-Propylthiouracil
NSC 6498
NSC 70461
Procasil
Propacil
propiltiouracilo
Propycil
Propyl-Thiorist
Propylthiorit
propylthiouracil
Propylthiouracile
Propyl-Thyracil
Prothiucil
Prothiurone
Prothycil
Prothyran
Protiural
Thiuragyl
Thyreostat II
URACIL, 4-PROPYL-2-THIO-
Uracil, 6-propyl-2-thio-
DTXSID5021209PR:Q6EWH2tyrosine-protein kinase fyna (zebrafish)GO:0005623cellUBERON:0000970eyePCO:0000001population of organismsGO:0004713protein tyrosine kinase activityGO:0008283cell proliferationMP:0001297microphthalmiaD009026mortalityPCO:0000008population growth rateVT:0002090vision trait2decreased1increased7functional changeRosmarinic acid2021-05-28T07:38:122021-05-28T07:40:50Saracatinib2021-05-28T08:04:212021-05-28T08:09:51Staurosporine2021-05-28T08:12:212021-05-28T08:17:362,4-Dinitrophenol2016-11-29T18:42:272016-11-29T18:42:27Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone2020-11-12T17:59:282020-11-12T17:59:28Carbonyl cyanide m-chlorophenyl hydrazone2020-11-12T17:59:472020-11-12T17:59:47Pentachlorophenol2020-11-12T17:59:122020-11-12T17:59:12Triclosan2020-11-12T18:00:072020-11-12T18:00:07Emodin2020-11-20T13:48:582020-11-20T13:48:58Malonoben2020-11-27T14:43:472020-11-27T14:43:47Diethylaminobenzaldehyde2019-05-22T05:17:552019-05-22T05:17:55Citral2019-05-22T05:18:072019-05-22T05:18:07Ethanol2018-04-05T06:38:482018-04-05T06:38:48Propylthiouracil2016-11-29T18:42:222016-11-29T18:42:22WCS_7955zebrafishWCS_9606human10116rat10090mouseWikiUser_22all speciesWCS_90988fathead minnowInhibition of FynaInhibition of FynaMolecular<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Src family kinases (SFKs) include nine members (i.e., Src, Fyn, Yes, Blk, Yrk, Fgr, Hck, Lck and Lyn) and regulate multiple signal transduction pathways involved in growth, proliferation, differentiation, migration, metabolism and apoptosis, interacting with a diverse array of molecules, including growth factor receptors, cell–cell adhesion receptors, integrins and steroid hormone receptors (Schenone et al., 2007). Protein kinases enable transfer of γ phosphate of ATP to specific amino acids of protein substrates (tyrosine, serine, threonine, or even histidine residues) (Saito, 2001). There are two major groups of tyrosine kinases: receptor and nonreceptor tyrosine kinases. Nonreceptor tyrosine kinases (cytoplasmatic proteins) are important components of signaling pathways through different receptors such as receptor tyrosine kinases, G-protein coupled receptors, or T-cell receptors (TCR) on the cell surface (Hanrs & Hunter, 1995). </span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Fyna (Src family tyrosine kinase A) is a nonreceptor tyrosine kinase. It is involved in several processes, including adherens junction maintenance and gastrulation. Fyna localizes to the cytosol and the nucleus. It is expressed in the central nervous system, olfactory placode, peripheral olfactory organ, and retina. Human ortholog(s) of this gene are implicated in Alzheimer's disease and schizophrenia. Zebrafish Fyna gene is orthologous to human FYN (FYN proto-oncogene, Src family tyrosine kinase) (<em>ZFIN Gene: Fyna</em>, n.d.) and shares 89% sequence identity (full length sequence and kinase domain) with the human FYN gene (Challa & Chatti, 2013). </span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">The Src family kinases are of a modular nature, consisting of a unique N-terminal sequence, three protein modules including the SH3, SH2, and kinase domains, and a C-terminal tail. The modules play an important role in enzyme reactions (Lamers et al., 2003). Fyna kinase activity, like that of other Src family kinases, is regulated by intramolecular interactions that depend on equilibrium between tyrosine phosphorylation and dephosphorylation. In the basal state, catalytic activity is constrained by engagement of the SH2 domain by a phosphorylated C-terminal tyrosine 531 (Krämer-Albers & White, 2011), after activation enzymes transmit signals from several surface receptors to target proteins by phosphorylating tyrosine residues (Sen and Johnson, 2011). Crystal structures of the SH2 and SH3 domains of the Fyna kinase reveal its binding specificity for peptide inhibitors (Morton et al., 1996; Mulhern et al., 1997). Binding of inhibitors to fyna domains inhibits its activity. Research in inhibition of Fyna kinase is mostly due its role in Alzheimer's disease (AD) and anti-inflamatory therapy (Löwenberg et al., 2005).</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">There are multiple known Fyna kinase inhibitors (see Evidence for perturbation by stressor).</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Changes in activity of Fyna kinase can be evaluated with enzyme-linked immunosorbent assay (ELISA). This type of ELISA method is based on kinase phosphorylation of an immobilized substrate, which is detected using anti-tyrosine phosphate antibody. The extent of the substrate phosphorylation can be measured by absorbance, fluorescence, or fluorescence polarization (Jelić et al., 2007).</span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Adp-Glo<sup>TM </sup>Kinase Assay can be used to measure Fyna kinase activity. The assay is well suited for measuring the effects chemical compounds have on the activity of a broad range of purified kinases, making it ideal for both primary screening as well as kinase selectivity profiling </span></span><span style="font-size:14px"><span style="font-family:"Times New Roman",serif">(Zegzouti <em>et al.</em>, 2009)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">.</span></span></p>
<p><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Theoretically, this MIE is applicable to any organisms with the Fyna kinase (zebrafish and other vertebrate models). While, in zebrafish Fyna inhibition was achieved with kinase dead (KD) point mutant of Fyna </span><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">(St. Clair et al., 2018), chemical inhibition most pertaining to this AOP was</span></span><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt"> mostly studied in human (Green et al., 2009; Jelić et al., 2007; Kinoshita et al., 2006; Lamers et al., 2003; Toullec et al., 1991) and mouse (Morisot et al., 2019; Nygaard et al., 2014) cell lines. </span></p>
UBERON:0000955brainCL:0000000cellHighUnspecificHighLarvaeHigh<p style="margin-left:40px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Challa, A. K., & Chatti, K. (2013). <em>Conservation and Early Expression of Zebrafish Tyrosine Kinases Support the Utility of Zebrafish as a Model for Tyrosine Kinase Biology</em>. <em>10</em>(3). https://doi.org/10.1089/zeb.2012.0781</span></span></p>
<p style="margin-left:40px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Green, T. P., Fennell, M., Whittaker, R., Curwen, J., Jacobs, V., Allen, J., Logie, A., Hargreaves, J., Hickinson, D. M., Wilkinson, R. W., Elvin, P., Boyer, B., Carragher, N., Plé, P. A., Bermingham, A., Holdgate, G. A., Ward, W. H. J., Hennequin, L. F., Davies, B. R., & Costello, G. F. (2009). Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. <em>Molecular Oncology</em>, <em>3</em>(3), 248–261. https://doi.org/10.1016/j.molonc.2009.01.002</span></span></p>
<p style="margin-left:40px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Hanrs, S. K., & Hunter, T. (1995). <em>The eukaryotic protein kinase superfamily: idnase. (catalytic) domam structure and classification</em>. https://doi.org/10.1096/fasebj.9.8.7768349</span></span></p>
<p style="margin-left:40px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Jelić, D., Mildner, B., Koštrun, S., Nujić, K., Verbanac, D., Čulić, O., Antolović, R., & Brandt, W. (2007). Homology modeling of human Fyn kinase structure: Discovery of rosmarinic acid as a new Fyn kinase inhibitor and in Silico study of its possible binding modes. <em>Journal of Medicinal Chemistry</em>, <em>50</em>(6), 1090–1100. https://doi.org/10.1021/jm0607202</span></span></p>
<p style="margin-left:40px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Kinoshita, T., Matsubara, M., Ishiguro, H., Okita, K., & Tada, T. (2006). Structure of human Fyn kinase domain complexed with staurosporine. <em>Biochemical and Biophysical Research Communications</em>, <em>346</em>(3), 840–844. https://doi.org/10.1016/j.bbrc.2006.05.212</span></span></p>
<p style="margin-left:40px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Krämer-Albers, E.-M., & White, R. (2011). From axon-glial signalling to myelination: the integrating role of oligodendroglial Fyn kinase. <em>Cell. Mol. Life Sci.</em> https://doi.org/10.1007/s00018-010-0616-z</span></span></p>
<p style="margin-left:40px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Lamers, M. B. A. C., Antson, A. A., Hubbard, R. E., Scott, R. K., & Williams, D. H. (2003). <em>Structure of the Protein Tyrosine Kinase Domain of C-terminal Src Kinase (CSK) in Complexwith Staurosporine</em>. <em>J. Mol. Bi</em>(285), 713–725. papers2://publication/uuid/CBF6FE3B-FE88-4A68-9E4A-EC387CF85D43</span></span></p>
<p style="margin-left:40px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Löwenberg, M., Tuynman, J., Bilderbeek, J., Gaber, T., Buttgereit, F., Van Deventer, S., Peppelenbosch, M., & Hommes, D. (2005). Rapid immunosuppressive effects of glucocorticoids mediated through Lck and Fyn. <em>Blood</em>, <em>106</em>(5), 1703–1710. https://doi.org/10.1182/blood-2004-12-4790</span></span></p>
<p style="margin-left:40px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Morisot, N., Berger, A. L., Phamluong, K., Cross, A., & Ron, D. (2019). The Fyn kinase inhibitor, AZD0530, suppresses mouse alcohol self-administration and seeking. <em>Addiction Biology</em>, <em>24</em>(6), 1227–1234. https://doi.org/10.1111/adb.12699</span></span></p>
<p style="margin-left:40px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Nygaard, H. B., Van Dyck, C. H., & Strittmatter, S. M. (2014). Fyn kinase inhibition as a novel therapy for Alzheimer’s disease. <em>Alzheimer’s Research and Therapy</em>, <em>6</em>(1), 1–8. https://doi.org/10.1186/alzrt238</span></span></p>
<p style="margin-left:40px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Saito, H. (2001). Histidine phosphorylation and two-component signaling in eukaryotic cells. <em>Chemical Reviews</em>, <em>101</em>(8), 2497–2509. https://doi.org/10.1021/cr000243+</span></span></p>
<p style="margin-left:40px"><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif">Sen, B., Johnson, F.M., 2011. Regulation of Src Family Kinases in Human Cancers. J. Signal Transduct. 2011, 1–14. https://doi.org/10.1155/2011/865819</span></span></p>
<p style="margin-left:40px"><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">St. Clair, R. M., Emerson, S. E., D’Elia, K. P., Weir, M. E., Schmoker, A. M., Ebert, A. M., & Ballif, B. A. (2018). Fyn-dependent phosphorylation of PlexinA1 and PlexinA2 at conserved tyrosines is essential for zebrafish eye development. <em>FEBS Journal</em>, <em>285</em>(1), 72–86. https://doi.org/10.1111/febs.14313</span></span></p>
<p style="margin-left:40px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Toullec, D., Pianetti, P., Coste, H., Bellevergue, P., Grand-Perret, T., Ajakane, M., Baudet, V., Boissin, P., Boursier, E., Loriolle, F., Duhamel, L., Charon, D., & Kirilovsky, J. (1991). The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. <em>Journal of Biological Chemistry</em>, <em>266</em>(24), 15771–15781. https://doi.org/10.1016/s0021-9258(18)98476-0</span></span></p>
<p style="margin-left:40px"><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif"><span style="font-size:14px">Zegzouti, H. <em>et al.</em> (2009) ‘ADP-Glo: A bioluminescent and homogeneous adp monitoring assay for Kinases’, <em>Assay and Drug Development Technologies</em>, 7(6), pp. 560–572. doi: 10.1089/adt.2009.0222</span>.</span></span></p>
<p style="margin-left:40px"><em><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">ZFIN Gene: fyna</span></span></em><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">. (n.d.). Retrieved March 14, 2021, from https://zfin.org/ZDB-GENE-030903-5#phenotype</span></span></p>
2021-05-28T05:31:452021-12-12T12:07:25Inhibition of Plxna2Inhibition of Plxna2Molecular<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Plexins (Plxns) are the receptors encoded by the members of the plexin gene family. They are primary transducers of vertebrate semaphorin (Sema) signals. The vertebrate plexins are subdivided into four subfamilies comprising four type A plexins, three type B plexins, plexin C1 (PlEXC1) and plexin D1(Neufeld & Kessler, 2008; Tamagnone et al., 1999). The plexins are transmembrane receptors distinguished by the presence of a split gTPase-activating (gAP) cytoplasmic domain (Oinuma et al., 2004). Semaphorins are members of a large gene family of secreted and membrane-anchored proteins. There are eight subclasses of Semas. Semas 1 and 2 are found in invertebrates, 3–7 are found in vertebrates, and Sema V is found in the genome of non-neurotropic DNA viruses. They were initially characterized as axon guidance factors and are divided into eight subfamilies. The receptors belonging to the plexin family function as semaphorin receptors (Neufeld & Kessler, 2008). Semas were initially discovered with respect to their role as repulsive guidance cues for migrating axons, although it is now appreciated that they have much broader roles in development. Semas and Plxns have tissue-specific expression patterns, and many Semas can signal through multiple Plxn family members (Luo et al., 1993). </span></p>
<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Plxna2 is predicted to have semaphorin receptor activity. Involved in optic vesicle formation, predicted to localize to integral component of plasma membrane and semaphorin receptor complex. Is expressed in several structures, including brain; hatching gland; olfactory field; optic vesicle; and retina and is critical to zebrafish eye development. Orthologous to human PLXNA2 (plexin A2)(</span><em>ZFIN Gene: Plxna2</em><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">, n.d.).</span></p>
<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Sema-Plxn signaling regulates cellular processes such as cytoskeletal dynamics, proliferation, and differentiation. However, the receptor-proximal signaling mechanisms driving Sema-Plxn signal transduction are only partially understood. Plxn tyrosine phosphorylation is thought to play an important role in these signaling events as receptor and nonreceptor tyrosine kinases have been shown to interact with Plxn receptors (St. Clair et al., 2018). Phosphorylation is one of the fundamental mechanisms of cell signaling and regulation of cell growth, proliferation, differentiation, metabolism, neural function, etc. (Hanrs & Hunter, 1995; Johnson & Lewis, 2010; Mellado et al., 2001). Tyrosine phosphorylation is a pivotal post-translational protein modification that regulates intracellular signalling. Therefore, phosphorylation of tyrosines in the intracellular domain of plex-ins could determine or modify their interactions with additional signal transducers (Franco & Luca Tamagnone, 2008).</span></p>
<p dir="ltr"><span style="background-color:transparent; color:#333333; font-family:Calibri,sans-serif; font-size:11pt">Phosphorylation changes of Plxna2 tyrosine can be detected directly using western blot and indirectly by using ELISA method to measure Plxna2 activity. There are several antibodies available commercially. </span></p>
<p dir="ltr"><span style="background-color:transparent; color:#333333; font-family:Calibri,sans-serif; font-size:11pt">In (St. Clair et al., 2018) study, Fyn kinase dependent phosphorylation of plxna2 was measured with western blotting using α-Fyn (rabbit mAb), α-Flag M2 (mouse mAb), α-phosphotyrosine 4G10 (mouse mAb), and α-Src pY416 (rabbit mAb). The following secondary antibodies were used: α-rabbit-HRP (goat IgG), α-mouse-HRP (goat IgG), or for immunoprecipitation samples, α-mouse- HRP Light Chain Specific (goat IgG) .</span></p>
<p><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Key event described here has been primarily established in zebrafish models (Emerson et al., 2017; St. Clair et al., 2018).</span></p>
UBERON:0004128optic vesicleCL:0000000cellHighUnspecificHighLarvaeHigh<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Emerson, S. E., St. Clair, R. M., Waldron, A. L., Bruno, S. R., Duong, A., Driscoll, H. E., Ballif, B. A., McFarlane, S., & Ebert, A. M. (2017). Identification of target genes downstream of semaphorin6A/PlexinA2 signaling in zebrafish. <em>Developmental Dynamics</em>, <em>246</em>(7), 539–549. https://doi.org/10.1002/dvdy.24512</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Franco, M., & Luca Tamagnone, &. (2008). review Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive. <em>EMBO Reports</em>, <em>9</em>, 865–871. https://doi.org/10.1038/embor.2008.139</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Hanrs, S. K., & Hunter, T. (1995). <em>The eukaryotic protein kinase superfamily: idnase. (catalytic) domam structure and classification</em>. https://doi.org/10.1096/fasebj.9.8.7768349</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Johnson, L. N., & Lewis, R. J. (2010). ChemInform Abstract: Structural Basis for Control by Phosphorylation. <em>ChemInform</em>, <em>32</em>(40), no--no. https://doi.org/10.1002/chin.200140284</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Luo, Y., Raible, D., & Raper, J. A. (1993). <em>Collapsin : A Protein in Brain That Induces the Collapse and Paralysis of Neuronal Growth Cones</em>. <em>75</em>(1984), 217–227.</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Mellado, M., Rodríguez-Frade, J. M., Mañes, S., & Martínez-A., C. (2001). Chemokine signaling and functional responses: The role of receptor dimerization and TK pathway activation. <em>Annual Review of Immunology</em>, <em>19</em>, 397–421. https://doi.org/10.1146/annurev.immunol.19.1.397</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Neufeld, G., & Kessler, O. (2008). The semaphorins: Versatile regulators of tumour progression and tumour angiogenesis. <em>Nature Reviews Cancer</em>, <em>8</em>(8), 632–645. https://doi.org/10.1038/nrc2404</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Oinuma, I., Ishikawa, Y., Katoh, H., & Negishi, M. (2004). The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. <em>Science</em>, <em>305</em>(5685), 862–865. https://doi.org/10.1126/science.1097545</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">St. Clair, R. M., Emerson, S. E., D’Elia, K. P., Marion, W. E., Schmoker, A. M., Ebert, A. M., & Ballif, B. A. (2018). Fyn-dependent phosphorylation of PlexinA1 and PlexinA2 at conserved tyrosines is essential for zebrafish eye development. <em>FEBS Journal</em>, <em>285</em>(1), 72–86. https://doi.org/10.1111/febs.14313</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Tamagnone, L., Artigiani, S., Chen, H., He, Z., Ming, G. L., Song, H. J., Chedotal, A., Winberg, M. L., Goodman, C. S., Poo, M. M., Tessier-Lavigne, M., & Comoglio, P. M. (1999). Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. <em>Cell</em>, <em>99</em>(1), 71–80. https://doi.org/10.1016/S0092-8674(00)80063-X</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><em>ZFIN Gene: plxna2</em>. (n.d.). Retrieved March 15, 2021, from http://zfin.org/ZDB-GENE-090311-6</span></span></p>
2021-05-28T05:37:082021-10-07T13:43:56Overexpression of rasl11bOverexpression of rasl11bMolecular<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Rasl11b is a member of the small GTPase protein family with a high degree of similarity to RAS proteins (Stolle et al., 2007). Predicted to have GTP binding activity and GTPase activity. Involved in mesendoderm development. Predicted to localize to membrane. Is expressed in several structures, including axis; central nervous system; presumptive ectoderm; shield; and tail bud. Orthologous to human RASL11B (RAS like family 11 member B) (</span><em>ZFIN Gene: Rasl11b</em><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">, n.d.). The Rasl11b protein is highly conserved among vertebrates, sharing on average 94% homology with its mammalian orthologs (Pézeron et al., 2008)</span></p>
<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Rasl11b is highly conserved in vertebrates and is atypical to most Ras-like family members in two ways. First, it is cytosolic and lacks carboxy terminal lipid modification sites which allow for membrane anchoring (Pezeron et al., 2008). Second, it has a lower GTPase activity than Ras, and is more often in its active GTP-bound state (Colicelli, 2004). Ras proteins are well known to be involved in the mitogen-activated protein kinase (MAPK) pathway, therefore, it is hypothesized that Rasl11b acts as a negative regulator of MAPK by outcompeting Ras for its effectors such as Raf, leading to decreases in RPC proliferation seen in morphant zebrafish embryos (Emerson et al., 2017).</span></p>
<p><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Overexpression can be measured with reverse transcription polymerase chain reaction (RT-PCR). This technique is primarily used to measure the amount of specific RNA which is achieved by monitoring the amplification reaction using fluorescence, a technique called real-time PCR or quantitative PCR (qPCR) (Wong & Medrano, 2005). Combined RT-PCR and qPCR are routinely used for analysis of gene expression.</span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">The relationships described herein have been primarily established in zebrafish models (Emerson et al., 2017). Evidence for this KE was also provided for humans (Colicelli, 2004; He et al., 2018).</span></span></p>
HighUnspecificHighLarvaeHigh<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Colicelli, J. (2004). Human RAS superfamily proteins and related GTPases. <em>Science’s STKE : Signal Transduction Knowledge Environment</em>, <em>2004</em>(250). https://doi.org/10.1126/stke.2502004re13</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Emerson, S. E., St. Clair, R. M., Waldron, A. L., Bruno, S. R., Duong, A., Driscoll, H. E., Ballif, B. A., McFarlane, S., & Ebert, A. M. (2017). Identification of target genes downstream of semaphorin6A/PlexinA2 signaling in zebrafish. <em>Developmental Dynamics</em>, <em>246</em>(7), 539–549. https://doi.org/10.1002/dvdy.24512</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">He, H., Dai, J., Zhuo, R., Zhao, J., Wang, H., Sun, F., Zhu, Y., & Xu, D. (2018). Study on the mechanism behind lncRNA MEG3 affecting clear cell renal cell carcinoma by regulating miR-7/RASL11B signaling. <em>Journal of Cellular Physiology</em>, <em>233</em>(12), 9503–9515. https://doi.org/10.1002/jcp.26849</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Pézeron, G., Lambert, G., Dickmeis, T., Strä Hle, U., Dé, F., Rosa, R. M., & Mourrain, P. (2008). Rasl11b Knock Down in Zebrafish Suppresses One-Eyed-Pinhead Mutant Phenotype. <em>PLoS ONE</em>. https://doi.org/10.1371/journal.pone.0001434</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Stolle, K., Schnoor, M., Fuellen, G., Spitzer, M., Cullen, P., & Lorkowski, S. (2007). Cloning, genomic organization, and tissue-specific expression of the RASL11B gene. <em>Biochimica et Biophysica Acta - Gene Structure and Expression</em>, <em>1769</em>(7–8), 514–524. https://doi.org/10.1016/j.bbaexp.2007.05.005</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Wong, M. L., & Medrano, J. F. (2005). <em>Real-time PCR for mRNA quantitation</em>. <em>39</em>(1), 75–85. https://doi.org/10.2144/05391RV01</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif"><em>ZFIN Gene: rasl11b</em>. (n.d.). Retrieved March 19, 2021, from http://zfin.org/ZDB-GENE-040426-793</span></span></p>
2021-05-28T05:38:592021-12-08T11:47:20Decrease, Cell proliferationDecrease, Cell proliferationCellular<p style="text-align:justify">Decreased cell proliferation describes the outcome of reduced cell division and cell growth. Cell proliferation is considered the main mechanism of tissue and organismal growth (Conlon 1999). Decreased cell proliferation has been associated with abnormal growth-factor signaling and cellular energy depletion (DeBerardinis 2008).</p>
<p style="text-align:justify">Multiple types of <em>in vitro</em> bioassays can be used to measure this key event:</p>
<ul>
<li>ToxCast high-throughput screening bioassays such as “BSK_3C_Proliferation”, “BSK_CASM3C_Proliferation” and “BSK_SAg_Proliferation” can be used to measure cell proliferation status.</li>
<li>Commercially available methods such as the well-established 5-bromo-2’-deoxyuridine (BrdU) (Raza 1985; Muir 1990) or 5-ethynyl-2’-deoxyuridine (EdU) assay. Both assays measure DNA synthesis in dividing cells to indicate proliferation status.<!--![endif]----></li>
</ul>
<p style="text-align:justify"><strong>Taxonomic applicability domain</strong></p>
<p>This key event is in general applicable to all eukaryotes, as most organisms are known to use cell proliferation to achieve growth.</p>
<p> </p>
<p><strong>Life stage applicability domain</strong></p>
<p>This key event is in general applicable to all life stages. As cell proliferation not only occurs in developing organisms, but also in adults.</p>
<p> </p>
<p><strong>Sex applicability domain</strong></p>
<p>This key event is sex-unspecific, as both genders use the same cell proliferation mechanisms.</p>
CL:0000000cellHighUnspecificHighEmbryoHighJuvenileHighHighHighHigh<p style="text-align:justify">Conlon I, Raff M. 1999. Size control in animal development. <em>Cell</em> 96:235-244. DOI: 10.1016/s0092-8674(00)80563-2.</p>
<p style="text-align:justify">DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. 2008. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. <em>Cell Metabolism</em> 7:11-20. DOI: <a href="https://doi.org/10.1016/j.cmet.2007.10.002">https://doi.org/10.1016/j.cmet.2007.10.002</a>.</p>
<p style="text-align:justify">Muir D, Varon S, Manthorpe M. 1990. An enzyme-linked immunosorbent assay for bromodeoxyuridine incorporation using fixed microcultures. <em>Analytical Biochemistry</em> 185:377-382. DOI: <a href="https://doi.org/10.1016/0003-2697(90)90310-6">https://doi.org/10.1016/0003-2697(90)90310-6</a>.</p>
<p style="text-align:justify">Raza A, Spiridonidis C, Ucar K, Mayers G, Bankert R, Preisler HD. 1985. Double labeling of S-phase murine cells with bromodeoxyuridine and a second DNA-specific probe. <em>Cancer Research</em> 45:2283-2287.</p>
2020-11-12T17:57:082020-12-07T06:55:47Decreased, Eye sizeDecreased, Eye sizeOrgan<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Animals show a wide variation in relative eye size (compared to body size) both within and between species. Eye size is directly related to visual ability. Eye size, and in particular the eye to body ratio, gives a lot of information about the quality of vision of the individual but also about its lifestyle. For example, eye size provides information on nocturnal and diurnal lifestyles in mammals (Kirk, 2006). Previous studies of eye design suggest a common organizing principle about how the activity pattern is reflected in the size and shape of the eyes (Hall, 2008). </span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Large eyes generally have greater visual sensitivity as they have relatively large corneas and lenses, e.g. in primates (e.g (Kirk, 2006; Ross and Kirk, 2007), birds (e.g (Brooke et al., 1999; Hall, 2008), lizards (Hall, 2008), fish (e.g. (Bejarano-Escobar et al., 2010; Karvonen and Seppälä, 2008) and other species. Increasing the size of the whole eye can increase resolution or sensitivity without having to decrease the other. For example, a larger eye with a longer focal length may be more sensitive without loss of acuity, or it may be more acute without loss of sensitivity. However, a constraint for large eyes is that they must always fit inside an animal's head and are associated with increased development and maintenance costs (Caves et al., 2017). </span></span></p>
<p style="text-align:justify"><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Microphthalmia is a congenital ocular deformation characterized by abnormally small eyes, with or without structural abnormalities </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Le et al., 2012)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">. Microphthalmia can occur as a consequence of a number of potential mechanisms, including but not limited to general developmental delay, increased cell death, reduced cell proliferation, and reduced cell differentiation within the developing eye </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Stenkamp et al., 2002)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">.</span></span></p>
<ul>
<li>Use of plasticine spherical ball (Brooke et al., 1999)</li>
<li>Ocular biometry (Kang and Wildsoet, 2016)</li>
<li>Relative eye size: larger corneal diameters relative to the axial length or larger eye diameter relative to body length (Baumann et al., 2016; Hall, 2008) determined by morphological analysis with electromicroscopy or analysis of digital images</li>
<li>Morphological live imaging + Aqueous outflow tract visualization (Chawla et al., 2018)</li>
</ul>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Taxonomic applicability: Applicable to a large range of species<span style="color:#5b9bd5"><em>. </em></span>For instance, eye length is positively correlated with visual acuity across mammals (Heesy and Hall 2010; Veilleux and Kirk 2014), birds (Hall and Heesy 2011), and fishes (Baumann et al., 2016; Caves et al., 2017; Corral-López et al., 2017).</span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Sex applicability: Difference in male/female probably due to general differences in body size, highlighted by some studies (Corral-López et al., 2017; Svanbäck and Johansson, 2019). </span></span></p>
UBERON:0000970eyeNot SpecifiedLarval developmentNot Specified<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Baumann, L., Ros, A., Rehberger, K., Neuhauss, S.C.F., Segner, H., 2016. Thyroid disruption in zebrafish (Danio rerio) larvae: Different molecular response patterns lead to impaired eye development and visual functions. Aquat. Toxicol. 172, 44–55. https://doi.org/10.1016/j.aquatox.2015.12.015</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Bejarano-Escobar, R., Blasco, M., DeGrip, W.J., Oyola-Velasco, J.A., Martín-Partido, G., Francisco-Morcillo, J., 2010. Eye development and retinal differentiation in an altricial fish species, the senegalese sole (Solea senegalensis, Kaup 1858). J. Exp. Zool. Part B Mol. Dev. Evol. 314 B, 580–605. https://doi.org/10.1002/jez.b.21363</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Brooke, M.D.L., Hanley, S., Laughlin, S.B., 1999. The scaling of eye size with body mass in birds. Proc. R. Soc. B Biol. Sci. 266, 405–412. https://doi.org/10.1098/rspb.1999.0652</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Caves, E.M., Sutton, T.T., Johnsen, S., 2017. Visual acuity in ray-finned fishes correlates with eye size and habitat. J. Exp. Biol. 220, 1586–1596. https://doi.org/10.1242/jeb.151183</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Chawla, B., Swain, W., Williams, A.L., Bohnsack, B.L., 2018. Retinoic acid maintains function of neural crest–derived ocular and craniofacial structures in adult zebrafish. Investig. Ophthalmol. Vis. Sci. 59, 1924–1935. https://doi.org/10.1167/iovs.17-22845</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Corral-López, A., Garate-Olaizola, M., Buechel, S.D., Kolm, N., Kotrschal, A., 2017. On the role of body size, brain size, and eye size in visual acuity. Behav. Ecol. Sociobiol. 71. https://doi.org/10.1007/s00265-017-2408-z</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Hall, M.I., 2008. Comparative analysis of the size and shape of the lizard eye. Zoology 111, 62–75. https://doi.org/10.1016/j.zool.2007.04.003</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Kang, P., Wildsoet, C.F., 2016. Acute and short-term changes in visual function with multifocal soft contact lens wear in young adults. Contact Lens Anterior Eye 39, 133–140. https://doi.org/10.1016/j.clae.2015.09.004</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Karvonen, A., Seppälä, O., 2008. Eye fluke infection and lens size reduction in fish: A quantitative analysis. Dis. Aquat. Organ. 80, 21–26. https://doi.org/10.3354/dao01918</span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Kashyap, B., Frederickson, L.C., & Stenkamp, D.L., 2008. Mechanisms for persistent microphthalmia following ethanol exposure during retinal neurogenesis in zebrafish embryos. Vis. Neurosci. 24(3), 409–421. https://doi.org/10.1017/S0952523807070423</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Kirk, E.C., 2006. Effects of activity pattern on eye size and orbital aperture size in primates. J. Hum. Evol. 51, 159–170. https://doi.org/10.1016/j.jhevol.2006.02.004</span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Le, H.G., Dowling, J.E., & Cameron, D.J., 2012. Early retinoic acid deprivation in developing zebrafish results in microphthalmia. Vis. Neurosci</span></span>.<span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> 29(4–5), 219–228. https://doi.org/10.1017/S0952523812000296</span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Marsh-Armstrong, N., Mccaffery, P., Gilbert, W., Dowling, J.E., & Dräger, U.C., 1994. Retinoic acid is necessary for development of the ventral retina in zebrafish.</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> Proc. Natl. Acad. Sci. U S A</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">. <em>91</em>(15), 7286–7290. https://doi.org/10.1073/pnas.91.15.7286</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Ross, C.F., Kirk, E.C., 2007. Evolution of eye size and shape in primates. J. Hum. Evol. 52, 294–313. https://doi.org/10.1016/j.jhevol.2006.09.006</span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Stenkamp, D.L., Frey, R.A., Mallory, D.E., & Shupe, E.E., 2002. Embryonic Retinal Gene Expression in Sonic-You Mutant Zebrafish. Dev. Dyn., 225, 344–350. https://doi.org/10.1002/dvdy.10165</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Svanbäck, R., Johansson, F., 2019. Predation selects for smaller eye size in a vertebrate: Effects of environmental conditions and sex. Proc. R. Soc. B Biol. Sci. 286. https://doi.org/10.1098/rspb.2018.2625</span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Wold, M., Beckmann, M., Poitra, S., Espinoza, A., Longie, R., Mersereau, E., Darland, D.C., Darland, T., 2017. The longitudinal effects of early developmental cadmium exposure on conditioned place preference and cardiovascular physiology in zebrafish. Aquat. Toxicol. 191, 73–84. https://doi.org/10.1016/j.aquatox.2017.07.017</span></span></p>
2021-05-11T05:32:332021-06-24T13:59:54Increased MortalityIncreased MortalityPopulation<p><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Increased mortality refers to an increase in the number of individuals dying in an experimental replicate group or in a population over a specific period of time.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="font-size:11pt"><span style="color:#212529"><span style="background-color:white">Mortality of animals is generally observed as cessation of the heart beat, breathing (gill or lung movement) and locomotory movements. Mortality is typically measured by observation. Depending on the size of the organism, instruments such as microscopes may be used. The reported metric is mostly the mortality rate: the number of deaths in a given area or period, or from a particular cause.</span></span></span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="font-size:11pt"><span style="color:#212529"><span style="background-color:white">Depending on the species and the study setup, mortality can be measured:</span></span></span></span></span></span></p>
<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:11pt"><span style="color:#212529"><span style="background-color:white">in the lab by recording mortality during exposure experiments</span></span></span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:11pt"><span style="color:#212529"><span style="background-color:white">in dedicated setups simulating a realistic situation such as mesocosms or drainable ponds for aquatic species</span></span></span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:11pt"><span style="color:#212529"><span style="background-color:white">in the field, for example by determining age structure after one capture, or by capture-mark-recapture efforts. The latter is a method commonly used in ecology to estimate an animal population's size where it is impractical to count every individual.</span></span></span></span></span></li>
</ul>
<p>All living things are susceptible to mortality.</p>
ModerateUnspecificHighAll life stagesHigh2016-11-29T18:41:242022-07-08T07:32:26Decrease, Population growth rateDecrease, Population growth ratePopulation<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">A population can be defined as a group of interbreeding organisms, all of the same species, occupying a specific space during a specific time (Vandermeer and Goldberg 2003, Gotelli 2008). As the population is the biological level of organization that is often the focus of ecological risk</span> <span style="color:black">assessments, population growth rate (and hence population size over time) is important to consider within the context of applied conservation practices.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">If N is the size of the population and t is time, then the population growth rate (dN/dt) is proportional to the instantaneous rate of increase, r, which measures the per capita rate of population increase over a short time interval. Therefore, r, is a difference between the instantaneous birth rate (number of births per individual per unit of time; b) and the instantaneous death rate (number of deaths per individual per unit of time; d) [Equation 1]. Because r is an instantaneous rate, its units can be changed via division. For example, as there are 24 hours in a day, an r of 24 individuals/(individual x day) is equal to an r of 1 individual/(individual/hour) (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020). </span></span></span></span></p>
<p style="margin-left:144px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Equation 1: r = b - d</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">This key event refers to scenarios where r < 0 (instantaneous death rate exceeds instantaneous birth rate).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Examining r in the context of population growth rate:</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● A population will decrease to extinction when the instantaneous death rate exceeds the instantaneous birth rate (r < 0). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black"> ● The smaller the value of r below 1, the faster the population will decrease to zero. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● A population will increase when resources are available and the instantaneous birth rate exceeds the instantaneous death rate (r > 0)</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black"> ● The larger the value that r exceeds 1, the faster the population can increase over time </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● A population will neither increase or decrease when the population growth rate equals 0 (either due to N = 0, or if the per capita birth and death rates are exactly balanced). For example, the per capita birth and death rates could become exactly balanced due to density dependence and/or to the effect of a stressor that reduces survival and/or reproduction (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Effects incurred on a population from a chemical or non-chemical stressor could have an impact directly upon birth rate (reproduction) and/or death rate (survival), thereby causing a decline in population growth rate. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● Example of direct effect on r: Exposure to 17b-trenbolone reduced reproduction (i.e., reduced b) in the fathead minnow over 21 days at water concentrations ranging from 0.0015 to about 41 mg/L (Ankley et al. 2001; Miller and Ankley 2004). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Alternatively, a stressor could indirectly impact survival and/or reproduction. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● Example of indirect effect on r: Exposure of non-sexually differentiated early life stage fathead minnow to the fungicide prochloraz has been shown to produce male-biased sex ratios based on gonad differentiation, and resulted in projected change in population growth rate (decrease in reproduction due to a decrease in females and thus recruitment) using a population model. (Holbech et al., 2012; Miller et al. 2022)</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Density dependence can be an important consideration:</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● The effect of density dependence depends upon the quantity of resources present within a landscape. A change in available resources could increase or decrease the effect of density dependence and therefore cause a change in population growth rate via indirectly impacting survival and/or reproduction. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● This concept could be thought of in terms of community level interactions whereby one species is not impacted but a competitor species is impacted by a chemical stressor resulting in a greater availability of resources for the unimpacted species. In this scenario, the impacted species would experience a decline in population growth rate. The unimpacted species would experience an increase in population growth rate (due to a smaller density dependent effect upon population growth rate for that species). </span> </span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Closed versus open systems:</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● The above discussion relates to closed systems (there is no movement of individuals between population sites) and thus a declining population growth rate cannot be augmented by immigration. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● When individuals depart (emigrate out of a population) the loss will diminish population growth rate. </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Population growth rate applies to all organisms, both sexes, and all life stages.</span></span></span></span></p>
<p> </p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Population growth rate (instantaneous growth rate) can be measured by sampling a population over an interval of time (i.e. from time t = 0 to time t = 1). The interval of time should be selected to correspond to the life history of the species of interest (i.e. will be different for rapidly growing versus slow growing populations). The population growth rate, r, can be determined by taking the difference (subtracting) between the initial population size, N</span><sub><span style="font-size:9pt"><span style="color:black">t=0 </span></span></sub><span style="color:black">(population size at time t=0), and the population size at the end of the interval, N</span><sub><span style="font-size:9pt"><span style="color:black">t=1 </span></span></sub><span style="color:black">(population size at time t = 1), and then subsequently dividing by the initial population size. </span></span></span></span></p>
<p style="margin-left:96px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Equation 2: r = (N</span><sub><span style="font-size:9pt"><span style="color:black">t=1 </span></span></sub><span style="color:black">- N</span><sub><span style="font-size:9pt"><span style="color:black">t=0</span></span></sub><span style="color:black">) / N</span><sub><span style="font-size:9pt"><span style="color:black">t=0</span></span></sub></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">The diversity of forms, sizes, and life histories among species has led to the development of a vast number of field techniques for estimation of population size and thus population growth over time (Bookhout 1994, McComb et al. 2021). </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● For stationary species an observational strategy may involve dividing a habitat into units. After setting up the units, samples are performed throughout the habitat at a select number of units (determined using a statistical sampling design) over a time interval (at time t = 0 and again at time t = 1), and the total number of organisms within each unit are counted. The numbers recorded are assumed to be representative for the habitat overall, and can be used to estimate the population growth rate within the entire habitat over the time interval. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● For species that are mobile throughout a large range, a strategy such as using a mark-recapture method may be employed (i.e. tags, bands, transmitters) to determine a count over a time interval (at time = 0 and again at time =1). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Population growth rate can also be estimated using mathematical model constructs (for example, ranging from simple differential equations to complex age or stage structured matrix projection models and individual based modeling approaches), and may assume a linear or nonlinear population increase over time (Caswell 2001, Vandermeer and Goldberg 2003, Gotelli 2008, Murray and Sandercock 2020). The AOP framework can be used to support the translation of pathway-specific mechanistic data into responses relevant to population models and output from the population models, such as changing (declining) population growth rate, can be used to assess and manage risks of chemicals (Kramer et al. 2011). As such, this translational capability can increase the capacity and efficiency of safety assessments both for single chemicals and chemical mixtures (Kramer et al. 2011). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Some examples of modeling constructs used to investigate population growth rate:</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● A modeling construct could be based upon laboratory toxicity tests to determine effect(s) that are then linked to the population model and used to estimate decline in population growth rate. Miller et al. (2007) used concentration–response data from short term reproductive assays with fathead minnow (<em>Pimephales promelas</em>) exposed to endocrine disrupting chemicals in combination with a population model to examine projected alterations in population growth rate. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● A model construct could be based upon a combination of effects-based monitoring at field sites (informed by an AOP) and a population model. Miller et al. (2015) applied a population model informed by an AOP to project declines in population growth rate for white suckers (Catostomus commersoni) using observed changes in sex steroid synthesis in fish exposed to a complex pulp and paper mill effluent in Jackfish Bay, Ontario, Canada. Furthermore, a model construct could be comprised of a series of quantitative models using KERs that culminates in the estimation of change (decline) in population growth rate. </span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● A quantitative adverse outcome pathway (qAOP) has been defined as a mathematical construct that models the dose–response or response–response relationships of all KERs described in an AOP (Conolly et al. 2017, Perkins et al. 2019). Conolly et al. (2017) developed a qAOP using data generated with the aromatase inhibitor fadrozole as a stressor and then used it to predict potential population‐level impacts (including decline in population growth rate). The qAOP modeled aromatase inhibition (the molecular initiating event) leading to reproductive dysfunction in fathead minnow (Pimephales promelas) using 3 computational models: a hypothalamus–pituitary–gonadal axis model (based on ordinary differential equations) of aromatase inhibition leading to decreased vitellogenin production (Cheng et al. 2016), a stochastic model of oocyte growth dynamics relating vitellogenin levels to clutch size and spawning intervals (Watanabe et al. 2016), and a population model (Miller et al. 2007).</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● Dynamic energy budget (DEB) models offer a methodology that reverse engineers stressor effects on growth, reproduction, and/or survival into modular characterizations related to the acquisition and processing of energy resources (Nisbet et al. 2000, Nisbet et al. 2011). Murphy et al. (2018) developed a conceptual model to link DEB and AOP models by interpreting AOP key events as measures of damage-inducing processes affecting DEB variables and rates.</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">● Endogenous Lifecycle Models (ELMs), capture the endogenous lifecycle processes of growth, development, survival, and reproduction and integrate these to estimate and predict expected fitness (Etterson and Ankley, 2021). AOPs can be used to inform ELMs of effects of chemical stressors on the vital rates that determine fitness, and to decide what hierarchical models of endogenous systems should be included within an ELM (Etterson and Ankley, 2021).</span></span></span></span></p>
<p> </p>
<p>Consideration of population size and changes in population size over time is potentially relevant to all living organisms.</p>
Not SpecifiedUnspecificNot SpecifiedAll life stagesHigh<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Ankley GT, Jensen KM, Makynen EA, Kahl MD, Korte JJ, Hornung MW, Henry TR, Denny JS, Leino RL, Wilson VS, Cardon MD, Hartig PC, Gray LE. 2003. Effects of the androgenic growth promoter 17b-trenbolone on fecundity and reproductive endocrinology of the fathead minnow. Environ. Toxicol. Chem. 22: 1350–1360.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Bookhout TA. 1994. Research and management techniques for wildlife and habitats. The Wildlife Society, Bethesda, Maryland. 740 pp.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Caswell H. 2001. Matrix Population Models. Sinauer Associates, Inc., Sunderland, MA, USA</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Cheng WY, Zhang Q, Schroeder A, Villeneuve DL, Ankley GT, Conolly R. 2016. Computational modeling of plasma vitellogenin alterations in response to aromatase inhibition in fathead minnows. Toxicol Sci 154: 78–89.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Conolly RB, Ankley GT, Cheng W-Y, Mayo ML, Miller DH, Perkins EJ, Villeneuve DL, Watanabe KH. 2017. Quantitative adverse outcome pathways and their application to predictive toxicology. Environ. Sci. Technol. 51: 4661-4672.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Etterson MA, Ankley GT. 2021. Endogenous Lifecycle Models for Chemical Risk Assessment. Environ. Sci. Technol. 55: 15596-15608. </span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Gotelli NJ, 2008. A Primer of Ecology. Sinauer Associates, Inc., Sunderland, MA, USA.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Holbech H, Kinnberg KL, Brande-Lavridsen N, Bjerregaard P, Petersen GI, Norrgren L, Orn S, Braunbeck T, Baumann L, Bomke C, Dorgerloh M, Bruns E, Ruehl-Fehlert C, Green JW, Springer TA, Gourmelon A. 2012 Comparison of zebrafish (<em>Danio rerio</em>) and fathead minnow <em>(Pimephales promelas</em>) as test species in the Fish Sexual Development Test (FSDT). Comp. Biochem. Physiol. C Toxicol. Pharmacol. 155: 407–415.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Kramer VJ, Etterson MA, Hecker M, Murphy CA, Roesijadi G, Spade DJ, Stromberg JA, Wang M, Ankley GT. </span><span style="color:black">2011. Adverse outcome pathways and risk assessment: Bridging to population level effects. Environ. Toxicol. Chem. 30, 64-76.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">McComb B, Zuckerberg B, Vesely D, Jordan C. 2021. Monitoring Animal Populations and their Habitats: A Practitioner's Guide. Pressbooks, Oregon State University, Corvallis, OR Version 1.13, 296 pp. </span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Miller DH, Villeneuve DL, Santana Rodriguez KJ, Ankley GT. 2022. A multidimensional matrix model for predicting the effect of male biased sex ratios on fish populations. Environmental Toxicology and Chemistry 41(4): 1066-1077.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Miller DH, Tietge JE, McMaster ME, Munkittrick KR, Xia X, Griesmer DA, Ankley GT. 2015. </span><span style="color:black">Linking mechanistic toxicology to population models in forecasting recovery from chemical stress: A case study from Jackfish Bay, Ontario, Canada. Environmental Toxicology and Chemistry 34(7): 1623-1633.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Miller DH, Jensen KM, Villeneuve DE, Kahl MD, Makynen EA, Durhan EJ, Ankley GT. 2007. </span><span style="color:black">Linkage of biochemical responses to population-level effects: A case study with vitellogenin in the fathead minnow (<em>Pimephales promelas</em>). Environ Toxicol Chem 26: 521–527.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Miller DH, Ankley GT. 2004. Modeling impacts on populations: Fathead minnow (<em>Pimephales promelas</em>) exposure to the endocrine disruptor 17b-trenbolone as a case study. Ecotox Environ Saf 59: 1–9.</span></span></span></li>
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2016-11-29T18:41:242023-01-03T09:09:06Altered, Visual functionAltered, Visual functionOrgan<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">The decrease in visual function can have different aspects, such as loss of chromatic vision, changes in eye movements, differences in sensitivity to light, but also changes in the retinal pigment epithelium (RPE) that may be related to a decrease in visual function (Strauss, 2005). The visual system is highly variable from one species to another, and this variability is a key factor influencing animal behaviour (Corral-López et al., 2017).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Decreases in these visual functions can have a strong impact on behaviour, leading to changes in individual response and abilities in the environment, including, for example, perception of food or avoidance of predators. Variation in the visual system can also influence learning tasks when visual stimuli are used (Corral-López et al., 2017).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Studies have detected visual impairments in fish at different temperatures (Babkiewicz et al., 2020) after treatment with the endocrine disruptor propylthiouracil (Baumann et al 2016 ), after chronic dietary selenomethionine exposure (Raine et al 2016), exposure to PCBs (Zhang et al, 2015) or deiodinase knockdown (Houbrechts et al 2016, Vancamp et al 2018).</span></span></span></span></p>
<p><br />
</p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Measurements of visual function can be performed at the level of neuronal activity:</span></span></span></span></p>
<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Electroretinography (Chrispell et al., 2015)</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Analysis of neural activity in the optic tectum can be quantified as the ratio of phosphorylated extracellular signal–regulated kinase (ERK) to total ERK in the optic tectum using immunofluorescent antibodies (Randlett et al., 2015, Dehnert et al., 2019).</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Babkiewicz et al. (2020) used an advanced technique to display an artificial prey on a miniature OLED screen and use functional calcium imaging with light sheet microscopy to visualize a neural response in the optic tectum.</span></span></li>
</ul>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Other measurements are performed at the level of the eyes:</span></span></span></span></p>
<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Opto Kinetic response, OKR (similar protocol for Rat/mice (Segura et al., 2018), fish (Zou et al., 2010) and humans (Kang and Wildsoet, 2016)). The OKR is a visually-mediated assay in which an individual will respond to alternating black and white stripes by exhibiting eye saccades, eye movements without coordinated body movements, in the same direction as rotating stripes. An eye saccade relies on the ability to rapidly move the eye from focusing on one external target to the next in a repeated manner (Magnuson et al., 2020). Optokinetic tracking has a robust performance and does not require training the animal, allowing for the quick assessment (and at earlier ages) of visual features such as visual acuity (VA) and contrast sensitivity (CS)11–14. </span></span></li>
</ul>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Yet other studies use assessment of vision-related behaviours: </span></span></span></span></p>
<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Opto Motor Reponses, OMR. OMR tracks the ability of fish to swim in the direction of a perceived motion when presented with a whole-field stimulus (Neuhauss, 2003), (Gould et al., 2017)).</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Light-dark transition or vision startle response: reaction to change in light intensity (light sensitivity) (Brastrom et al., 2019)</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Black-white preference test (Baumann et al., 2016)</span></span></span></li>
</ul>
<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Diverse Mobility assay including Tracking, touch-evoked escape-response assays, Swirl assays, locomotion assay, swimming activity, phototactic swimming activity assay, induced locomotor response (LLR) (Baumann et al., 2016; Gao et al., 2015; Zhao et al., 2014, Dehnert et al., 2019).</span></span></span></li>
</ul>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Taxonomic applicability</span></strong><span style="color:black">: Visual function decrease can be evaluated in </span><span style="color:black">a </span><span style="color:black">wide range of species including mammals, amphibians, fish and humans. Evaluation of these visual function modification</span><span style="color:black">s</span><span style="color:black"> change according to the species and its environment.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Life-stage applicability</span></strong><span style="color:black">: Vision plays a crucial role in the early life stages of most species, as timing of eye development and establishment of functional vision is essential for perception of food or avoidance of predators for example (Carvalho et al., 2002).</span> <span style="color:black">The first visual responses based on retinal functionality appear around 70 hpf in zebrafish (Schmitt and Dowling 1999). It is plausible to assume that alterations of the eye structure would result in altered visual function across all life stages, but such alterations are most likely to occur during the development of the normal eye structure, which occurs in the embryo-eleutheroembryo phase. Some studies have also shown a decrease in vision related to age (Brastrom et al., 2019; Martínez-Roda et al., 2016; Segura et al., 2018) including on visual acuity, visual fields, colour vision and dark adaptation, are well documented (Hennelly et al, 1998).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Sex applicability</span></strong><span style="color:black">: Sex does not seem relevant for most of the visual function decreases observed in different studies. Differences according to the sex of the individuals have however been reported concerning the basic visual capacities (e.g. color perception, contrast sensitivity, visual acuity, motion perception,...) but also concerning the frequency of certain diseases influencing these diminished visual functions, notably in humans (Vanston and Strother, 2017).</span></span></span></span></p>
<p><br />
</p>
UBERON:0000970eyeModerateUnspecificHighEmbryoModerateJuvenileHighLarvaeHigh<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000">Baumann, L., Ros, A., Rehberger, K., Neuhauss, S. C. F., & Segner, H. (2016). Thyroid disruption in zebrafish (Danio rerio) larvae: Different molecular response patterns lead to impaired eye development and visual functions. Aquatic Toxicology, 172, 44–55. https://doi.org/10.1016/j.aquatox.2015.12.015</span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000">Babkiewicz, E., Bazała, M., Urban, P., Maszczyk, P., Markowska, M., & Maciej Gliwicz, Z. (2020). The effects of temperature on the proxies of visual detection of Danio rerio larvae: observations from the optic tectum. Biology Open, 9(7). https://doi.org/10.1242/BIO.047779</span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000">Brastrom, L.K., Scott, C.A., Dawson, D. V., Slusarski, D.C., 2019. A High-Throughput Assay for Congenital and Age-Related Eye Diseases in Zebrafish. Biomedicines 7, 28. https://doi.org/10.3390/biomedicines7020028</span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000">Carvalho, P.S.M., Noltie, D.B., Tillitt, D.E., 2002. Ontogenetic improvement of visual function in the medaka Oryzias latipes based on an optomotor testing system for larval and adult fish. Anim. Behav. 64, 1–10. https://doi.org/10.1006/anbe.2002.3028</span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000">Chrispell JD, Rebrik TI, Weiss ER. 2015. Electroretinogram Analysis of the Visual Response in Zebrafish Larvae. Jove-Journal of Visualized Experiments(97).</span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000">Corral-López, A., Garate-Olaizola, M., Buechel, S.D., Kolm, N., Kotrschal, A., 2017. On the role of body size, brain size, and eye size in visual acuity. Behav. Ecol. Sociobiol. 71. https://doi.org/10.1007/s00265-017-2408-z</span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000">Dehnert GK, Karasov WH, Wolman MA. 2019. 2,4-Dichlorophenoxyacetic acid containing herbicide impairs essential visually guided behaviors of larval fish. Aquatic Toxicology 209:1-12.</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Gao, D., Wu, M., Wang, C., Wang, Y., Zuo, Z., 2015. Chronic exposure to low benzo[a]pyrene level causes neurodegenerative disease-like syndromes in zebrafish (Danio rerio). Aquat. Toxicol.</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Gould, C. J., Wiegand, J. L., & Connaughton, V. P. (2017). Acute developmental exposure to 4-hydroxyandrostenedione has a long-term effect on visually-guided behaviors. Neurotoxicology and Teratology, 64, 45–49. https://doi.org/10.1016/j.ntt<a href="https://doi.org/10.1016/j.ntt.2017.10.003">.</a>2017.10.003</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Hennelly, M. L., Barbur, J. L., Edgar, D. F., & Woodward, E. G. (1998). The effect of age on the light scattering characteristics of the eye. Ophthalmic and Physiological Optics, 18(2), 197–203. https://doi.org/10.1046/j.1475-1313.1998.00333.x</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Houbrechts, A. M., Vergauwen, L., Bagci, E., Van houcke, J., Heijlen, M., Kulemeka, B., Hyde, D. R., Knapen, D., & Darras, V. M. (2016). Deiodinase knockdown affects zebrafish eye development at the level of gene expression, morphology and function. Molecular and Cellular Endocrinology, 424, 81–93. https://doi.org/10.1016/j.mce.2016.01.018</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Kang, P., & Wildsoet, C. F. (2016). Acute and short-term changes in visual function with multifocal soft contact lens wear in young adults. Contact Lens and Anterior Eye, 39(2), 133–140. https://doi.org/10.1016/j.clae.2015.09.004</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Magnuson, J., Bautista, N., Lucero, J., Lund, A., Xu, E. G., Schlenk, D., Burggren, W., & Roberts, A. P. (2020). Exposure to crude oil induces retinal apoptosis and impairs visual function in fish. Environmental Science & Technology. https://doi.org/10.1021/acs.est.9b07658</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Martínez-Roda, J. A., Vilaseca, M., Ondategui, J. C., Aguirre, M., & Pujol, J. (2016). Effects of aging on optical quality and visual function. Clinical and Experimental Optometry, 99(6), 518–525. https://doi.org/10.1111/cxo.12369</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Neuhauss, S. C. F. (2003). Behavioral genetic approaches to visual system development and function in zebrafish. Journal of Neurobiology, 54(1), 148–160. https://doi.org/10.1002/neu.10165</span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000">Raine, J. C., Lallemand, L., Pettem, C. M., & Janz, D. M. (2016). Effects of Chronic Dietary Selenomethionine Exposure on the Visual System of Adult and F1 Generation Zebrafish (Danio rerio). Bulletin of Environmental Contamination and Toxicology, 97(3), 331–336. https://doi.org/10.1007/s00128-016-1849-9</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Randlett O, Wee CL, Naumann EA, Nnaemeka O, Schoppik D, Fitzgerald JE, Portugues R, Lacoste AMB, Riegler C, Engert F et al. . 2015. Whole-brain activity mapping onto a zebrafish brain atlas. Nature Methods 12(11):1039-1046.</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Schmitt, E. A., & Dowling, J. E. (1994). Early‐eye morphogenesis in the zebrafish, Brachydanio rerio. Journal of Comparative Neurology, 344(4), 532–542. https://doi.org/10.1002/cne.903440404</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Segura, F., Arines, J., Sánchez-Cano, A., Perdices, L., Orduna-Hospital, E., Fuentes-Broto, L., & Pinilla, I. (2018). Development of optokinetic tracking software for objective evaluation of visual function in rodents. Scientific Reports, 8(1), 1–11. https://doi.org/10.1038/s41598-018-28394-x</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Strauss, O. (2005). The retinal pigment epithelium in visual function. Physiological Reviews, 85(3), 845–881.https://doi.org/10.1152/physrev.00021.2004</span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000">Vancamp, P., Bourgeois, N. M. A., Houbrechts, A. M., & Darras, V. M. (2019). Knockdown of the thyroid hormone transporter MCT8 in chicken retinal precursor cells hampers early retinal development and results in a shift towards more UV/blue cones at the expense of green/red cones. Experimental Eye Research,178(September 2018), 135–147. https://doi.org/10.1016/j.exer.2018.09.018</span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Zhang, X., Hong, Q., Yang, L., Zhang, M., Guo, X., Chi, X., & Tong, M. (2015). PCB1254 exposure contributes to the abnormalities of optomotor responses and influence of the photoreceptor cell development in zebrafish larvae. Ecotoxicology and Environmental Safety, 118, 133–138. https://doi.org/10.1016/j.ecoenv.2015.04.026</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Zhao, J., Xu, T., & Yin, D. Q. (2014). Locomotor activity changes on zebrafish larvae with different 2,2’,4,4’-tetrabromodiphenyl ether (PBDE-47) embryonic exposure modes. Chemosphere, 94, 53–61. https://doi.org/10.1016/j.chemosphere.2013.09.010</span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Zou, S. Q., Yin, W., Zhang, M. J., Hu, C. R., Huang, Y. bin, & Hu, B. (2010). Using the optokinetic response to study visual function of zebrafish. Journal of Visualized Experiments, 36, 5–8. https://doi.org/10.3791/1742</span></span></p>
2019-05-22T05:12:282022-07-08T07:30:5967554576-ecf4-471c-a530-745762d9ee06a2b33aa9-14a5-45f4-bb65-6e90c4f9ad06<p dir="ltr">Normally, Fyna phosphorylates Plxna2, allowing Plxna2 to effectively bind semaphorin signals. When Fyna is inhibited, the phosphorylation of Plxna2 is inhibited and the Plxna2 function as a semaphorin receptor is inhibited. </p>
<p><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Fyna (Src family tyrosine kinase A) is a non receptor tyrosine. Protein kinases enable transfer of γ phosphate of ATP to specific amino acids of protein substrates (tyrosine, serine, threonine, or even histidine residues) (Saito, 2001). Phosphorylation of certain tyrosine residues changes the enzymatic activity of tyrosine kinases and regulates specificity for substrate binding, localization, and recruitment of downstream signaling proteins (Hanrs & Hunter2, 1995). Plxna2 is one of the Fyna downstream signaling proteins. In mice Fyn was discovered to constitutively associate with and phosphorylate the intracellular region of Plxna1 and Plxna2 (Sasaki et al., 2002).</span></p>
<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Fyna (Src family tyrosine kinase A) induces phosphorylation of plexins (plxna2) (Sasaki et al., 2002;St. Clair et al., 2018 ). Inhibition of Fyna leads to reduced Plxna2 phosphorylation and results in inhibition of its activity.</span></p>
<p dir="ltr"> </p>
<ul>
<li dir="ltr" style="list-style-type:disc">
<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">To show that FYN induces PLXNA2 tyrosine phosphorylation HEK293 cells were transfected with expression plasmids encoding Flag-tagged PLXNA2 and either FYN wild-type (WT) or a kinase dead (KD) point mutant of Fyn. PLXNA2 showed prominent tyrosine phosphorylation when FYN WT was coexpressed and this phosphorylation was absent when FYN KD was coexpressed. These results are consistent with the findings of others (Sasaki et al., 2002) and demonstrate tyrosine phosphorylation events on Plxna2 that are induced by Fyna kinase activity (St. Clair et al., 2018).</span></p>
</li>
<li dir="ltr" style="list-style-type:disc">
<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Using zebrafish as a model organism, (St. Clair et al., 2018) investigated the <em>in vivo</em> functional significance of phosphorylation sites and found that Fyna-dependent Plxna2 phosphorylation is critical for zebrafish eye development. Fyna was shown to induce phosphorylation of two conserved sites on Plxna1 and Plxna2. Y1605 and Y1677 are the major Fyn-dependent sites of Plxna2 tyrosine phosphorylation.</span></p>
</li>
</ul>
<p dir="ltr">No data. </p>
<p>No known inconsistencies. </p>
<p>No data. </p>
HighUnspecificHighLarvaeHighHighHigh<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">KER described here has been established mostly in zebrafish and other vertebrate models. Research suggests that Fyn-dependent phosphorylation is a key feature of vertebrate Plxna1 and Plxna2 signal transduction which is essential for zebrafish eye development (St. Clair et al., 2018).</span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Hanrs, S. K., & Hunter, T. (1995). <em>The eukaryotic protein kinase superfamily: idnase. (catalytic) domain structure and classification</em>. https://doi.org/10.1096/fasebj.9.8.7768349</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Saito, H. (2001). Histidine phosphorylation and two-component signaling in eukaryotic cells. <em>Chemical Reviews</em>, <em>101</em>(8), 2497–2509. https://doi.org/10.1021/cr000243+</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">St. Clair, R. M., Emerson, S. E., D’Elia, K. P., Marion, W. E., Schmoker, A. M., Ebert, A. M., & Ballif, B. A. (2018). Fyn-dependent phosphorylation of PlexinA1 and PlexinA2 at conserved tyrosines is essential for zebrafish eye development. <em>FEBS Journal</em>, <em>285</em>(1), 72–86. https://doi.org/10.1111/febs.14313</span></span></p>
<p style="margin-left:32px"><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Sasaki, Y., Cheng, C., Uchida, Y., Nakajima, O., Ohshima, T., Yagi, T., Taniguchi, M., Nakayama, T., Kishida, R., Kudo, Y., Ohno, S., Nakamura, F., & Goshima, Y. (2002). Fyn and Cdk5 Mediate Semaphorin-3A Signaling, Which Is Involved in Regulation of Dendrite Orientation in Cerebral Cortex drite guidance in the cerebral cortex. We propose a signal transduction pathway in which Fyn and Cdk5 mediate neuronal guidance regula. <em>Neuron</em>, <em>35</em>, 907–920.</span></span></p>
<p><em><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> ZFIN Gene: plxna2</span></span></em><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">. (n.d.). Retrieved March 15, 2021, from http://zfin.org/ZDB-GENE-090311-6</span></span></p>
2021-05-28T06:03:172021-12-12T16:31:56a2b33aa9-14a5-45f4-bb65-6e90c4f9ad064a6cfd2a-77a5-4bfe-a7d2-3885831cf39e<p dir="ltr">Inhibition of Plxna2 activity leads to overexpression of <em>rasl11b</em>. </p>
<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Plexins (Plxns) are semaphorin (Sema) receptors that play important signaling roles, particularly in the developing nervous system and vasculature. It is known that Plexins have an intracellular split GAP (GTPase activating protein) domain that can regulate Ras-family small GTPases (Negishi et al., 2005; Pasterkamp, 2005). Small GTPases act as molecular switches: “on” when GTP-bound, and “off” when GDP-bound (Bos et al., 2007). GAPs increase GTP hydrolysis and thereby increase the “off,” GDP-bound form of the protein. Plxn intracellular GAP domains are inactive when Plxns are in inactive, open conformations. Upon Sema binding, PlxnAs undergo a conformational change, which forms an active GAP domain, in addition to activating downstream effector proteins (He et al., 2009). Phosphorylation is one of the fundamental mechanisms of cell signaling and regulation of cell growth, proliferation, differentiation, metabolism, neural function, etc (Hanrs & Hunter, 1995; Johnson & Lewis, 2010; Mellado et al., 2001). Therefore, phosphorylation of tyrosines in the intracellular domain of plex-ins could determine or modify their interactions with additional signal transducers (Franco & Luca Tamagnone, 2008). </span></p>
<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Rasl11b is negatively regulated downstream of Sema6a/Plxna2 signaling and when overexpressed, decreases RPC proliferation and eye size (Emerson et al., 2017). Rasl11b is a member of the small GTPase protein family with a high degree of similarity to RAS proteins (Stolle et al., 2007). The Rasl11b protein is highly conserved among vertebrates, sharing on average 94% homology with its mammalian orthologues (Pézeron et al., 2008). Ras proteins are well known to be involved in the mitogen-activated protein kinase (MAPK) pathway, therefore, it is hypothesized that Rasl11b acts as a negative regulator of MAPK by outcompeting Ras for its effectors such as Raf, leading to decreases in RPC proliferation seen in morphant embryos (Emerson et al., 2017).</span></p>
<p><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Rasl11b is negatively regulated downstream of Sema6a/Plxna2 signaling and when overexpressed, decreases retinal precursor cells proliferation and eye size (Emerson et al., 2017).</span></p>
<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Microarray analysis using RNA extracted from 18 somite zebrafish embryos deficient in either Sema6a or Plxna2 has enabled the identification of several downstream transcriptional targets of Sema6a/Plxna2 signaling during early stages of neuronal development. Further characterization of one of these genes, RAS-like, family 11, member B (<em>rasl11b</em>), revealed its role in regulating retinal progenitor cell (RPC) proliferation. Microarray results indicated that <em>rasl11b</em> has a 2.18 log-fold change (logFC) in <em>sema6a</em> morphants and a 1.58 logFC in <em>plxna2</em> morphants (Emerson et al., 2017). The microarray results were confirmed in independent experiments, using RT-PCR as readout (Emerson et al., 2017).</span></p>
<p>No data. </p>
<p>No known inconsistencies. </p>
<p>No data. </p>
HighUnspecificHighLarvaeHigh<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">The relationships described herein have been primarily established in zebrafish models </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Emerson et al., 2017; St. Clair et al., 2018)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">.</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Bos, J. L., Rehmann, H., & Wittinghofer, A. (2007). GEFs and GAPs: Critical Elements in the Control of Small G Proteins (DOI:10.1016/j.cell.2007.05.018). <em>Cell</em>, <em>130</em>(2), 385. https://doi.org/10.1016/j.cell.2007.07.001</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Emerson, S. E., St. Clair, R. M., Waldron, A. L., Bruno, S. R., Duong, A., Driscoll, H. E., Ballif, B. A., McFarlane, S., & Ebert, A. M. (2017). Identification of target genes downstream of semaphorin6A/PlexinA2 signaling in zebrafish. <em>Developmental Dynamics</em>, <em>246</em>(7), 539–549. https://doi.org/10.1002/dvdy.24512</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Franco, M., & Luca Tamagnone, &. (2008). review Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive. <em>EMBO Reports</em>, <em>9</em>, 865–871. https://doi.org/10.1038/embor.2008.139</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Hanrs, S. K., & Hunter, T. (1995). <em>The eukaryotic protein kinase superfamily: idnase. (catalytic) domain structure and classification</em>. https://doi.org/10.1096/fasebj.9.8.7768349</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">He, H., Yang, T., Terman, J. R., Zhang, X., & Kuriyan, J. (2009). <em>Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration</em>. https://doi.org/https://doi.org/10.1073/pnas.0906923106</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Johnson, L. N., & Lewis, R. J. (2010). ChemInform Abstract: Structural Basis for Control by Phosphorylation. <em>ChemInform</em>, <em>32</em>(40), no--no. https://doi.org/10.1002/chin.200140284</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Mellado, M., Rodríguez-Frade, J. M., Mañes, S., & Martínez-A., C. (2001). Chemokine signaling and functional responses: The role of receptor dimerization and TK pathway activation. <em>Annual Review of Immunology</em>, <em>19</em>, 397–421. https://doi.org/10.1146/annurev.immunol.19.1.397</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Negishi, M., Oinuma, I., & Katoh, H. (2005). Plexins: Axon guidance and signal transduction. <em>Cellular and Molecular Life Sciences</em>, <em>62</em>(12), 1363–1371. https://doi.org/10.1007/s00018-005-5018-2</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Pasterkamp, R. J. (2005). R-Ras fills another GAP in semaphorin signalling. <em>Trends in Cell Biology</em>, <em>15</em>(2), 61–64. https://doi.org/10.1016/j.tcb.2004.12.005</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Pézeron, G., Lambert, G., Dickmeis, T., Strä Hle, U., Dé, F., Rosa, R. M., & Mourrain, P. (2008). Rasl11b Knock Down in Zebrafish Suppresses One-Eyed-Pinhead Mutant Phenotype. <em>PLoS ONE</em>. https://doi.org/10.1371/journal.pone.0001434</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">St. Clair, R. M., Emerson, S. E., D’Elia, K. P., Marion, W. E., Schmoker, A. M., Ebert, A. M., & Ballif, B. A. (2018). Fyn-dependent phosphorylation of PlexinA1 and PlexinA2 at conserved tyrosines is essential for zebrafish eye development. <em>FEBS Journal</em>, <em>285</em>(1), 72–86. https://doi.org/10.1111/febs.14313</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Stolle, K., Schnoor, M., Fuellen, G., Spitzer, M., Cullen, P., & Lorkowski, S. (2007). Cloning, genomic organization, and tissue-specific expression of the RASL11B gene. <em>Biochimica et Biophysica Acta - Gene Structure and Expression</em>, <em>1769</em>(7–8), 514–524. https://doi.org/10.1016/j.bbaexp.2007.05.005</span></span></p>
2021-05-28T06:55:472021-12-12T16:34:544a6cfd2a-77a5-4bfe-a7d2-3885831cf39e99e6d15a-e520-4c96-aa08-f4f048623442<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Ras proteins are well known to be involved in the mitogen-activated protein kinase (MAPK) pathway, therefore, it is hypothesized that Rasl11b acts as a negative regulator of MAPK by outcompeting Ras for its effectors such as Raf, leading to decreases in retinal progenitor cells (RPCs) proliferation seen in morphant embryos (Emerson et al., 2017).</span></p>
<p><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Rasl11b is a member of the small GTPase protein family with a high degree of similarity to RAS proteins (Stolle et al., 2007). Orthologous to human <em>RASL11B</em> (RAS like family 11 member B) <span style="font-size:12px">(</span></span><span style="font-size:12px"><em>ZFIN Gene: Rasl11b</em></span><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt"><span style="font-size:12px">, n.d.).</span> The Rasl11b protein is highly conserved among vertebrates, sharing on average 94% homology with its mammalian orthologues (Pézeron et al., 2008). </span></p>
<p><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">It is hypothesized that Rasl11b acts as a negative regulator of MAPK by outcompeting Ras for its effectors such as Raf. After the overexpression of <em>rasl11b</em>, G0/G1 phase cell cycle arrest is induced and the proliferation of RPCs is inhibited (Emerson et al., 2017; He et al., 2018).</span></p>
<ul>
<li dir="ltr" style="list-style-type:disc">
<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">To determine if increased <em>rasl11b</em> expression contributes to decreased proliferation of RPCs, single-cell zebrafish embryos were injected with full-length <em>rasl11b</em> mRNA. Proliferation (pHH3) was visualized in the early eye field (rx3:GFP) of 18 somite embryos injected with 200 pg or 400 pg rasl11b mRNA. Overexpression of <em>rasl11b</em> resulted in decreased RPC proliferation in a dose-dependent manner. At 48 hpf, overexpression of <em>rasl11b</em> resulted in smaller eyes. (Emerson et al., 2017) show that <em>rasl11b</em> is negatively regulated downstream of Sema6a/Plxna2 signaling and when overexpressed, decreases RPC proliferation and eye size.</span></p>
</li>
<li dir="ltr" style="list-style-type:disc">
<p dir="ltr"><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">(Emerson et al., 2017) confirmed through morpholino knockdown, that Sema6a/Plxna2 signaling regulates proliferation and cohesive migration of RPCs in developing optic vesicles in zebrafish. Initial characterization of one gene, <em>rasl11b</em>, uncovered its contributing role to the proliferation of RPCs, providing insight into the mechanisms that control this key developmental process.</span><strong> </strong></p>
</li>
</ul>
<p><strong> </strong>No data.</p>
<ul>
</ul>
<p>No data.</p>
<p>No data.</p>
HighUnspecificHighLarvaeHigh<p><span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">The relationships described herein have been primarily established in zebrafish models (Emerson et al., 2017). Evidence is also provided for humans (He et al., 2018). Because rasl11b protein is highly conserved among vertebrates, sharing on average 94% homology with its mammalian orthologues this KE relationship could be translated to other vertebrates and mammals.</span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Emerson, S. E., St. Clair, R. M., Waldron, A. L., Bruno, S. R., Duong, A., Driscoll, H. E., Ballif, B. A., McFarlane, S., & Ebert, A. M. (2017a). Identification of target genes downstream of semaphorin6A/PlexinA2 signaling in zebrafish. <em>Developmental Dynamics</em>, <em>246</em>(7), 539–549. https://doi.org/10.1002/dvdy.24512</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">He, H., Dai, J., Zhuo, R., Zhao, J., Wang, H., Sun, F., Zhu, Y., & Xu, D. (2018). Study on the mechanism behind lncRNA MEG3 affecting clear cell renal cell carcinoma by regulating miR-7/RASL11B signaling. <em>Journal of Cellular Physiology</em>, <em>233</em>(12), 9503–9515. https://doi.org/10.1002/jcp.26849</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Pézeron, G., Lambert, G., Dickmeis, T., Strä Hle, U., Dé, F., Rosa, R. M., & Mourrain, P. (2008). Rasl11b Knock Down in Zebrafish Suppresses One-Eyed-Pinhead Mutant Phenotype. <em>PLoS ONE</em>. https://doi.org/10.1371/journal.pone.0001434</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Stolle, K., Schnoor, M., Fuellen, G., Spitzer, M., Cullen, P., & Lorkowski, S. (2007). Cloning, genomic organization, and tissue-specific expression of the RASL11B gene. <em>Biochimica et Biophysica Acta - Gene Structure and Expression</em>, <em>1769</em>(7–8), 514–524. https://doi.org/10.1016/j.bbaexp.2007.05.005</span></span></p>
<p><em><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">ZFIN Gene: rasl11b</span></span></em><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">. (n.d.). Retrieved March 19, 2021, from http://zfin.org/ZDB-GENE-040426-793</span></span></p>
2021-05-28T06:56:332021-12-12T16:40:4299e6d15a-e520-4c96-aa08-f4f0486234421ef12a20-6aa3-4765-8445-c48bf3a83d31<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Decrease in proliferation of retinal progenitor cells (RPCs) results in decreased eye size.</span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Decrease in eye size due to teratogenic insult or genetic abnormalities may result from a number of different mechanisms, including general developmental delay, increased cell death, decreased cell proliferation, or decreased retinal cell differentiation </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Stenkamp et al., 2002)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">.</span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Cell proliferation during retinal development adds volume to the eye, decrease of cell proliferation thus leads to decrease of eye volume.</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Some studies showed that changes in different genes lead to decreased eye size: </span></span></p>
<ul>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">In zebrafish Rasl11b is negatively regulated downstream of Sema6A/Plxna2. To achieve rasl11b overexpression 200 pg or 400 pg full-length zebrafish rasl11b mRNA was injected into single-cell embryos. At 48 hpf, overexpression of rasl11b resulted in reduced cell proliferation of RPC and consequently in smaller eyes (Emerson et al., 2017). </span></span></li>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Zebrafish/mouse heterozygous knockouts of rx3 (retinal homeobox gene 3) have an eyeless phenotype (Graw, 2010; Muranishi et al., 2012; Tucker et al., 2001). This gene acts upstream of or within animal organ development and cell fate specification and is critical for survival of progenitor cells during eye morphogenesis (Kennedy et al., 2004).</span></span></li>
<li><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">In mice Vsx2 gene is involved in neural retina development. Mice with impaired Vsx2 production have a small eye phenotype due to decreased proliferation of RPCs (Burmeister et al., 1996; Zagozewski et al., 2014). </span></span></li>
</ul>
<p>No data.</p>
<ul>
</ul>
<p>No data.</p>
<p>No data.</p>
HighUnspecificHighLarvaeHigh<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Evidence was provided for Zebrafish </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Emerson et al., 2017; Harding et al., 2021; Kashyap et al., 2008; Le et al., 2012)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">, mice </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Graw, 2019; Harding et al., 2021)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">, <em>Xenopus </em></span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Graw, 2010; Mathers et al., 1997)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> and humans </span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">(Harding & Moosajee, 2019; Verma & Fitzpatrick, 2007; Warburg, 1993)</span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">.</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Burmeister, M., Novak, J., Liang, M. Y., Basu, S., Ploder, L., Hawes, N. L., Vidgen, D., Hoover, F., Goldman, D., Kalnins, V. I., Roderick, T. H., Taylor, B. A., Hankin, M. H., & McInnes, R. R. (1996). Ocular retardation mouse caused by Chx10 homeobox null allele: Impaired retinal progenitor proliferation and bipolar cell differentiation. <em>Nature Genetics</em>, <em>12</em>(4), 376–384. https://doi.org/10.1038/ng0496-376</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Emerson, S. E., St. Clair, R. M., Waldron, A. L., Bruno, S. R., Duong, A., Driscoll, H. E., Ballif, B. A., McFarlane, S., & Ebert, A. M. (2017). Identification of target genes downstream of semaphorin6A/PlexinA2 signaling in zebrafish. <em>Developmental Dynamics</em>, <em>246</em>(7), 539–549. https://doi.org/10.1002/dvdy.24512</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Graw, J. (2010). Eye development. <em>Current Topics in Developmental Biology</em>, <em>90</em>(C), 343–386. https://doi.org/10.1016/S0070-2153(10)90010-0</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Graw, J. (2019). <em>Mouse models for microphthalmia, anophthalmia and cataracts</em>. <em>138</em>, 1007–1018. https://doi.org/10.1007/s00439-019-01995-w</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Harding, P., Lima Cunha, D., & Moosajee, M. (2021). Animal and cellular models of microphthalmia. <em>Ther Adv Rare Dis</em>, <em>2</em>, 1–34. https://doi.org/10.1177/2633004021997447</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Harding, P., & Moosajee, M. (2019). The Molecular Basis of Human Anophthalmia and Microphthalmia. <em>J. Dev. Biol.</em>, <em>7</em>(16). https://doi.org/10.3390/jdb7030016</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Kashyap, B., Frederickson, L. C., & Stenkamp, D. L. (2008). Mechanisms for persistent microphthalmia following ethanol exposure during retinal neurogenesis in zebrafish embryos. <em>Visual Neuroscience</em>, <em>24</em>(3), 409–421. https://doi.org/10.1017/S0952523807070423</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Kennedy, B. N., Stearns, G. W., Smyth, V. A., Ramamurthy, V., Van Eeden, F., Ankoudinova, I., Raible, D., Hurley, J. B., & Brockerhoff, S. E. (2004). Zebrafish rx3 and mab21l2 are required during eye morphogenesis. <em>Developmental Biology</em>, <em>270</em>(2), 336–349. https://doi.org/10.1016/j.ydbio.2004.02.026</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Le, H. G., Dowling, J. E., & Cameron, D. J. (2012). Early retinoic acid deprivation in developing zebrafish results in microphthalmia. <em>Visual Neuroscience</em>, <em>29</em>(4–5), 219–228. https://doi.org/10.1017/S0952523812000296</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Li, Z., Hu, M., Ochocinska, M. J., Joseph, N. M., & Easter, S. S. (2000). Modulation of Cell Proliferation in the Embryonic Retina of Zebrafish (Danio rerio). <em>Developmental Dynamics</em>, <em>219</em>(3), 391–401.</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Li, Z., Joseph, N. M., & Easter, S. S. (2000). <em>The Morphogenesis of the Zebrafish Eye, Including a Fate Map of the Optic Vesicle</em>.</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Mathers, P. H., Grinberg, A., Mahon, K. A., & Jamrich, M. (1997). The Rx homeobox gene is essential for vertebrate eye development. <em>Nature</em>, <em>387</em>(6633), 603–607. https://doi.org/10.1038/42475</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Muranishi, Y., Terada, K., & Furukawa, T. (2012). An essential role for Rax in retina and neuroendocrine system development. <em>Dev. Growth Differ.</em>, <em>54</em>, 341–348. https://doi.org/10.1111/j.1440-169X.2012.01337.x</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Stenkamp, D. L., Frey, R. A., Mallory, D. E., & Shupe, E. E. (2002). Embryonic Retinal Gene Expression in Sonic-You Mutant Zebrafish. <em>Developmental Dynamics</em>, <em>225</em>, 344–350. https://doi.org/10.1002/dvdy.10165</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Tucker, P., Laemle, L., Munson, A., Kanekar, S., Oliver, E. R., Brown, N., Schlecht, H., Vetter, M., & Glaser, T. (2001). The eyeless mouse mutation (ey1) removes an alternative start codon from the Rx/rax homeobox gene. <em>Genesis</em>, <em>31</em>(1), 43–53. https://doi.org/10.1002/gene.10003</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Verma, A. S., & Fitzpatrick, D. R. (2007). Anophthalmia and microphthalmia. <em>Orphanet Journal of Rare Diseases</em>, <em>2</em>, 47. https://doi.org/10.1186/1750-1172-2-47</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Warburg, M. (1993). Classification of microphthalmos and coloboma. <em>Journal of Medical Genetics</em>, <em>30</em>(8), 664–669. https://doi.org/10.1136/jmg.30.8.664</span></span></p>
<p style="margin-left:32px"><span style="font-size:11pt"><span style="font-family:"Calibri",sans-serif">Zagozewski, J. L., Zhang, Q., & Eisenstat, D. D. (2014). Genetic regulation of vertebrate eye development. <em>Clinical Genetics</em>, <em>86</em>(5), 453–460. https://doi.org/10.1111/cge.12493</span></span></p>
<p><em><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> ZFIN Gene: vsx2</span></span></em><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">. (n.d.). Retrieved March 27, 2021, from http://zfin.org/ZDB-GENE-001222-1</span></span></p>
2021-05-28T06:57:322021-08-07T13:43:161ef12a20-6aa3-4765-8445-c48bf3a83d31030052f6-d094-4f92-a4c3-56a02662857c<p dir="ltr"><strong>The link between eye size on the lifestyle of organisms (aquatic and/or terrestrial) is now proven by numerous studies. Therefore, the shape and size of the eyes is also related to the visual capacity of organisms.</strong></p>
<p><br />
</p>
<p dir="ltr"><strong>Increasing the size of the whole eye can increase resolution or sensitivity without having to decrease the other and inversely (Caves et al, 2017).</strong></p>
<p dir="ltr"><strong>Eye size, and in particular the eye to body ratio, gives a lot of information about the quality of vision of the individual but also about its lifestyle, e.g : nocturnal or diurnal species (Kirk, 2006). Previous studies of eye design suggest a common organizing principle about how the activity pattern is reflected in the size and shape of the eyes (Hall, 2008).</strong></p>
<p><br />
</p>
<p dir="ltr"><strong>Baumann et al., 2016 used propylthiouracil (PTU) and tetrabromobisphenol A (TBBPA) to disrupt the thyroid hormone system in zebrafish larvae. The exposure caused a reduction of eye size and a decrease in optokinetic response and increase in light preference of exposed larvae.</strong></p>
<p dir="ltr">Crowley-Perry et al. (2021) showed that transient, developmental exposure to sublethal and environmentally relevant concentrations of bisphenol A (BPA) alters larval eye morphology and visually guided behaviors. BPA exposure increased eye diameters and the number of larvae displaying a positive optomotor response (OMR). </p>
<p dir="ltr"><span style="font-size:12.0pt"><span style="font-family:"Calibri",sans-serif">Heijlen et al. (2014) showed that knockdown of Type 3 Iodothyronine Deiodinase reduced eye size in zebrafish embryos. Furthermore, D3-knockdown larvae spent significantly less time moving, and both embryos and larvae exhibited perturbed escape responses. </span></span></p>
<p><strong>Probably, the eye size is not the only determinizing factor for visual function. General morphology and structure appear to be essential.</strong></p>
Not Specified<p dir="ltr"><strong>Links between eyes size and visual function can be applicable to a wide range of species including mammal, amphibian, fish and human. Effect or form of this relationship change according to the environment and species. </strong></p>
<p dir="ltr"><strong>Life stage can also strongly influence this relationship. For example, recovery phases after early developmental exposure can decrease or reverse the effect (Baumann et al., 2019)</strong></p>
<p dir="ltr"><strong>Sex seems have no influence on this relationship. </strong></p>
<p><br />
</p>
<p dir="ltr"><strong>Baumann, L., Ros, A., Rehberger, K., Neuhauss, S. C. F., & Segner, H. (2016). Thyroid disruption in zebrafish (Danio rerio) larvae: Different molecular response patterns lead to impaired eye development and visual functions. Aquatic Toxicology, 172, 44–55. https://doi.org/10.1016/j.aquatox.2015.12.015</strong></p>
<p dir="ltr"><strong>Baumann, L., Segner, H., Ros, A., Knapen, D., & Vergauwen, L. (2019). Thyroid Hormone Disruptors Interfere with Molecular Pathways of Eye Development and Function in Zebrafish. International Journal of Molecular Sciences, 20(7), 1543. https://doi.org/10.3390/ijms20071543</strong></p>
<p dir="ltr"><strong>Corral-López, A., Garate-Olaizola, M., Buechel, S. D., Kolm, N., & Kotrschal, A. (2017). On the role of body size, brain size, and eye size in visual acuity. Behavioral Ecology and Sociobiology, 71(12). https://doi.org/10.1007/s00265-017-2408-z</strong></p>
<p dir="ltr"><strong>Hall, M. I. (2008). Comparative analysis of the size and shape of the lizard eye. Zoology, 111(1), 62–75. https://doi.org/10.1016/j.zool.2007.04.003</strong></p>
<p><br />
</p>
2021-05-11T05:38:342022-01-07T13:41:30030052f6-d094-4f92-a4c3-56a02662857ca68e5c1d-eb24-4e82-a142-aca6e1c143e8<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">In animals, whatever the taxa, visual abilities are strongly linked to their lifestyle (feeding, avoidance of predators, movement, protection....). When these capacities are impaired, they lead to reduced fitness and are therefore strongly linked to a decrease in survival, particularly in the early stages of life.</span></span></span></span></p>
<p><br />
</p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Decreases in visual functions can have a strong impact on behavior, leading to changes in individual response and abilities in the environment, including, for example, perception of food or avoidance of predators. Variation in the visual system can also influence learning tasks when visual stimuli are used (Corral-López et al., 2017). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Sensory drive has been implicated in speciation in various taxa, largely based on phenotype-environment correlations and signatures of selection in sensory genes, including </span><span style="color:black">vision</span> <span style="color:black">(Maan et al, 2017). </span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">It </span><span style="color:black">is biologically plausible</span> <span style="color:black">that an animal which has difficulties in finding food and avoiding predators will have lower survival chances in wildlife.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Only very few studies are available in which it was demonstrated that decreased visual capacities lead to reduced survival of the organism. In general, mortality is rarely assessed but survival-reducing factors (feeding, predation) are mainly investigated. Here we consider the work about different toxicants that disrupt complex fish behaviors, such as predator avoidance, reproductive, and social behaviors. Toxicant exposure often completely eliminates the performance of behaviors that are essential to fitness and survival in natural ecosystems, frequently after exposures of lesser magnitude than those causing significant mortality (Brown et al., 2004).</span></span></span></span></p>
<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Fuiman et al. (2006) specifically investigated the importance of several putative survival skills for escaping a predator. They first analysed routine swimming, acoustic startle stimulus and visual startle stimulus of red drum larvae and subsequently performed a predation experiment using the same larvae in the presence of a live predator. The authors found that the effectiveness of escape responses was almost 100% and thus responsiveness determined survival under predation. Of the different putative survival skills, only visual responsiveness was significantly correlated to escape potential, while others such as acoustic responsiveness were not significantly contributing to escape potential. Further investigation showed that only visual responsiveness differed significantly between poorly responding larvae and better responders.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Dehnert et al., 2019</span><span style="color:black">:</span><span style="color:black"> In zebrafish, 2, 4-Dichlorophenoxyacetic acid exposure during eye development impaired visual behavior, i.e. reduced prey capture. </span><span style="color:black">Additionally</span><span style="color:black">, exposed fish showed reduced neural activity within the optic tectum following prey exposure.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Besson et al., 2020 exposed metamorphosing convict surgeonfish to pharmacological treatments.</span> <span style="color:black">They performed a 10</span><sup><span style="font-size:9pt"><span style="color:black">−6 </span></span></sup><span style="color:black">M NH3 treatment (a TH antagonist) to achieve TH signal disruption and they observed an adverse outcome on retinal layer level. Repressed retinal development at both day 2 and day 5 with a 10-25 % decrease of bipolar cell density was detected. They followed up with a behavior test at day 2 with blacktail snapper as a predator and got the following results: </span></span></span></li>
</ul>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">1. In the test using chemical cues of the predator the NH3-treated fish did not discriminate between water sources, while control fish clearly avoided predator cues.</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">2. In the </span><span style="color:black">visual</span><span style="color:black"> cues test the NH3-treated fish showed no preference and spent 25 % more time in visual stimulus compared to controls.</span></span></span></span></p>
<p style="margin-left:48px; text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">3. In a survival predation test in an in situ arena they observed that day 2 NH3 treated fish exhibited 30% lower survival than d2 control fish.</span></span></span></span></p>
<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Furthermore Besson et al., 2020 conducted a Chlorpyrifos (CPF) treatment 30 μg L−1 and observed a significant reduction (25%) in T4 levels at day 2 in CPF30 fish, as well as significantly reduced T3 levels in CPF30 fish (28%) compared with control fish. CPF30 fish also exhibited reduced densities of bipolar cell (10%) of retinal layer and CPF30 fish experienced lower survival.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Flamarique et al. (2013) showed that thyroid hormone treatment impacted the development of the visual system in rainbow trout and reduced the distances and angles at which prey were located (variables that are known indicators of foraging performance). Using optical measurements and photon-catch calculations, the study showed that control rainbow trouts perceived prey (Daphnia) with greater contrast compared to thyroid-hormone-treated fish. Reduced foraging performance is likely to reduce survival in the wild.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Heijlen et al. (2014) showed that knockdown of Type 3 Iodothyronine Deiodinase, known to disrupt eye development (Houbrechts et al. (2016), causes embryos to spend significantly less time moving, and perturbs the escape response after a tactile stimulus. </span><span style="color:black">An inability to escape predators likely reduces survival in the wild.</span></span></span></li>
</ul>
<p><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">It is obvious that impaired vision leads to higher mortality, as the sense of sight is important for survival, and if it is impaired, feeding or escape becomes more difficult. However, the number of studies investigating this connection is limited. </span><span style="color:black">It is often unclear to what extent this relationship is determined by altered visual function versus other pathways such as alterations in muscle development or other factors contributing to these types of behaviour. </span><span style="color:black">Also, the natural conditions, which depend on many variables, are difficult to reproduce in the laboratory or to compare between different laboratories. </span></span></span></span></p>
ModerateUnspecificModerateAll life stagesHigh<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Taxonomic applicability: </span></strong><span style="color:black">The visual system of the fish (e.g., zebrafish) follows the typical organisation of vertebrates and is often used as a model to study human eye diseases. Although there are some differences, it is plausible to assume that visual function is important for survival across all vertebrates and invertebrates that have eyes.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Sex applicability: </span></strong><span style="color:black">Zebrafish are undifferentiated gonochorists since both sexes initially develop an immature ovary (Maack and Segner, 2003). Immature ovary development progresses until approximately the onset of the third week. Later, in female fish immature ovaries continue to develop further, while male fish undergo transformation of ovaries into testes. Final transformation into testes varies among male individuals, however finishes usually around 6 weeks post fertilization. Effects on mortality resulting from altered visual function are therefore expected to be independent of sex.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Life stage applicability: </span></strong><span style="color:black">It is plausible to assume that altered visual function of the eye would result in a higher mortality across all life stages. This could be especially true for the embryonic stages, the most sensitive stage of life. Vision plays a crucial role (in the early life stages) of most species, as eye development and establishment of functional vision is essential for perception of food or avoidance of predators for example (Carvalho et al., 2002).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:#212529">Babkiewicz, E., Bazała, M., Urban, P., Maszczyk, P., Markowska, M., & Maciej Gliwicz, Z. (2020). The effects of temperature on the proxies of visual detection of Danio rerio larvae: observations from the optic tectum. Biology Open, 9(7). https://doi.org/10.1242/BIO.047779</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:#212529">Besson, M., Feeney, W. E., Moniz, I., François, L., Brooker, R. M., Holzer, G., Metian, M., Roux, N., Laudet, V., & Lecchini, D. (2020). Anthropogenic stressors impact fish sensory development and survival via thyroid disruption. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-17450-8</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:#212529">Brown, S. B., Adams, B. A., Cyr, D. G., & Eales, J. G. (2004). Contaminant effects on the teleost fish thyroid. Environmental Toxicology and Chemistry, 23(7), 1680–1701. https://doi.org/10.1897/03-242</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:#212529">Carvalho, P. S. M., Noltie, D. B., & Tillitt, D. E. (2002). Ontogenetic improvement of visual function in the medaka Oryzias latipes based on an optomotor testing system for larval and adult fish. Animal Behaviour, 64(1), 1–10. https://doi.org/10.1006/anbe.2002.3028</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:#212529">Corral-López, A., Garate-Olaizola, M., Buechel, S. D., Kolm, N., & Kotrschal, A. (2017). On the role of body size, brain size, and eye size in visual acuity. Behavioral Ecology and Sociobiology, 71(12). https://doi.org/10.1007/s00265-017-2408-z</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:#212529">Dehnert, G. K., Karasov, W. H., & Wolman, M. A. (2019). 2,4-Dichlorophenoxyacetic acid containing herbicide impairs essential visually guided behaviors of larval fish. Aquatic Toxicology, 209(October 2018), 1–12. https://doi.org/10.1016/j.aquatox.2019.01.015</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:#212529">Flamarique IN. 2013. Opsin switch reveals function of the ultraviolet cone in fish foraging. Proceedings of the Royal Society B-Biological Sciences 280(1752).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:#212529">Fuiman LA, Rose KA, Cowan JH, Smith EP. 2006. Survival skills required for predator evasion by fish larvae and their relation to laboratory measures of performance. Animal Behaviour 71:1389-1399.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:#212529">Heijlen M, Houbrechts A, Bagci E, Van Herck S, Kersseboom S, Esguerra C, Blust R, Visser T, Knapen D, Darras V. 2014. Knockdown of type 3 iodothyronine deiodinase severely perturbs both</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:#212529">Houbrechts AM, Delarue J, Gabriels IJ, Sourbron J, Darras VM. 2016. Permanent Deiodinase Type 2 Deficiency Strongly Perturbs Zebrafish Development, Growth, and Fertility. Endocrinology 157(9):3668-3681.</span></span></span></span></p>
2021-05-11T05:27:512022-07-08T08:26:57a68e5c1d-eb24-4e82-a142-aca6e1c143e8805aa76d-cd2c-4ff0-b2a6-7dc03a6709c9<p><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Increased mortality in the reproductive population may lead to a declining population. This depends on the excess mortality due to the applied stressor and the environmental parameters such as food availability and predation rate. Most fish species are r-strategist, meaning they produce a lot of offspring instead of investing in parental care. This results in natural high larval mortality causing only a small percentage of the larvae to survive to maturity. If the excess larval mortality due to a stressor is small, the population dynamics might result in constant population size. Should the larval excess be more significant, or last on the long-term, this will affect the population. To calculate the long-term persistence of the population, population dynamic models should be used.</span></span></span></span></p>
<p><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Survival rate is an obvious determinant of population size and is therefore included in population modeling (e.g., Miller et al., 2020).</span></span></span></span></p>
<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Survival to reproductive maturity is a parameter of demographic significance. Assuming resource availability (i.e., food, habitat, etc.) is not limiting to the extant population, sufficient mortality in the reproductive population may ultimately lead to declining population trajectories.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Under some conditions, reduced larval survival may be compensated by reduced predation and increased food availability, and therefore not result in population decline (Stige et al., 2019).</span></span></li>
</ul>
<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">According to empirical data, combined with population dynamic models, feeding larvae are the crucial life stage in zebrafish (and other r-strategists) for the regulation of the population. (Schäfers et al., 1993)</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">In fathead minnow, natural survival of early life stages has been found to be highly variable and influential on population growth (Miller and Ankley, 2004)</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Rearick et al. (2018) used data from behavioural assays linked to survival trials and applied a modelling approach to quantify changes in antipredator escape performance of larval fathead minnows in order to predict changes in population abundance. This work was done in the context of exposure to an environmental oestrogen. Exposed fish had delayed response times and slower escape speeds, and were more susceptible to predation. Population modelling showed that this can result in population decline.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">In the context of fishing and fisheries, ample evidence of a link between increased mortality and a decrease of population size has been given. Important insights can result from the investigation of optimum modes of fishing that allow for maintaining a population (Alekseeva and Rudenko, 2018). Jacobsen and Essington (2018) showed the impact of varying predation mortality on forage fish populations.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Boreman (1997) reviewed methods for comparing the population-level effects of mortality in fish populations induced by pollution or fishing.</span></span></li>
</ul>
<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">The extent to which larval mortality affects population size could depend on the fraction of surplus mortality compared to a natural situation.</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">There are scenarios in which individual mortality may not lead to declining population size. These include instances where populations are limited by the availability of habitat and food resources, which can be replenished through immigration. Effects of mortality in the larvae can be compensated by reduced competition for resources (Stige et al., 2019).</span></span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">The direct impact of pesticides on migration behavior can be difficult to track in the field, and documentation of mortality during migration is likely underestimated (Eng 2017).</span></span></span></li>
</ul>
<ul>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Assuming other relevant demographic parameters are available, the effect of increased mortality rates on population status can be quantitatively predicted using standard population modeling approaches.</span></span></li>
<li><span style="font-size:12pt"><span style="font-family:Calibri,sans-serif">Stage population matrix models (Caswell, 2000) simulate population growth rates based on age-specific parameters and can be adapted to a range of species (Pinceel et al., 2016). For zebrafish, individually based models (IBM) have been developed to link responses at the individual level to the population level (Beaudouin et al., 2015). However, authors agree that survival is one of the most uncertain parameters in the model and more research on the topic is needed.</span></span></li>
</ul>
ModerateUnspecificHighAll life stagesHighHigh<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Taxonomic</span></strong><span style="color:black">: All organisms must survive to reproductive age in order to reproduce and sustain populations. The additional considerations related to survival made above are applicable to other fish species in addition to zebrafish and fathead minnows with the same reproductive strategy (r-strategist as described in the theory of MaxArthur and Wilson (1967). The impact of reduced survival on population size is even greater for k-strategists that invest more energy in a lower number of offspring.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Life stage</span></strong><span style="color:black">: Density dependent effects start to play a role in the larval stage of fish when free-feeding starts (Hazlerigg et al., 2014).</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><strong><span style="color:black">Sex</span></strong><span style="color:black">: This linkage is independent of sex.</span></span></span></span></p>
<p> </p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Alekseeva SM, Rudenko AI. 2018. Modeling of optimum fishing population. Marine Intellectual Technologies. 3(4):142-146.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Beaudouin, R., Goussen, B., Piccini, B., Augustine, S., Devillers, J., Brion, F., Pery, A.R., 2015. An individual-based model of zebrafish population dynamics accounting for energy dynamics. PloS one 10, e0125841.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Boreman J. 1997. Methods for comparing the impacts of pollution and fishing on fish populations. Transactions of the American Fisheries Society. 126(3):506-513.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Caswell, H., 2000. Matrix population models. Sinauer Sunderland, MA, USA.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Eng, M.L., Stutchbury, B.J.M. & Morrissey, C.A. Imidacloprid and chlorpyrifos insecticides impair migratory ability in a seed-eating songbird. Sci Rep 7, 15176 (2017)</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Hazlerigg, C.R., Lorenzen, K., Thorbek, P., Wheeler, J.R., Tyler, C.R., 2012. Density-dependent processes in the life history of fishes: evidence from laboratory populations of zebrafish Danio rerio. PLoS One 7, e37550.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Jacobsen NS, Essington TE. 2018. Natural mortality augments population fluctuations of forage fish. Fish and Fisheries. 19(5):791-797.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">MacArthur, R., Wilson, E., 1967. The Theory of Island Biogeography. Princeton: Princeton Univ. Press. 203 p.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Miller, D.H., Ankley, G.T., 2004. Modeling impacts on populations: fathead minnow (Pimephales promelas) exposure to the endocrine disruptor 17β-trenbolone as a case study. Ecotoxicology and Environmental Safety 59, 1-9.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Miller, D.H., Clark, B.W., Nacci, D.E. 2020. A multidimensional density dependent matrix population model for assessing risk of stressors to fish populations. Ecotoxicology and environmental safety 201, 110786</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Pinceel, T., Vanschoenwinkel, B., Brendonck, L., Buschke, F., 2016. Modelling the sensitivity of life history traits to climate change in a temporary pool crustacean. Scientific reports 6, 29451.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Rearick, D.C., Ward, J., Venturelli, P., Schoenfuss, H., 2018. Environmental oestrogens cause predation-induced population decline in a freshwater fish. Royal Society open science 5, 181065.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Schäfers, C., Oertel, D., Nagel, R., 1993. Effects of 3, 4-dichloroaniline on fish populations with differing strategies of reproduction. In: Braunbeck, T. , Hanke, W and Segner, H. (eds) Ecotoxicology and Ecophysiology, VCH, Weinheim, 133-146.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Stige, L.C., Rogers, L.A., Neuheimer, A.B., Hunsicker, M.E., Yaragina, N.A., Ottersen, G., Ciannelli, L., Langangen, Ø., Durant, J.M., 2019. Density‐and size‐dependent mortality in fish early life stages. Fish and Fisheries 20, 962-976.Hazlerigg, C.R.E., Tyler, C.R., Lorenzen, K., Wheeler, J.R., Thorbek, P., 2014. Population relevance of toxicant mediated changes in sex ratio in fish: An assessment using an individual-based zebrafish (Danio rerio) model. Ecological Modelling 280, 76-88.</span></span></span></span></p>
<p style="text-align:start"><span style="font-size:medium"><span style="font-family:Calibri,sans-serif"><span style="color:#000000"><span style="color:black">Stige, L.C., Rogers, L.A., Neuheimer, A.B., Hunsicker, M.E., Yaragina, N.A., Ottersen, G., Ciannelli, L., Langangen, O., Durant, J.M., 2019. Density- and size-dependent mortality in fish early life stages. Fish and Fisheries 20, 962-976.</span></span></span></span></p>
<p> </p>
2019-12-20T16:07:122022-07-08T08:29:35Inhibition of Fyna leading to increased mortality via decreased eye size (Microphthalmos)Inhibition of Fyna leading to increased mortality<p>Vid Modic<sup>1,2</sup>, Roman Li<sup>3</sup>, Ziva Ramsak<sup>2</sup>, Colette vom Berg<sup>3</sup>, Anze Zupanic<sup>2,3</sup></p>
<p><sup>1</sup>University of Ljubljana, Faculty of Chemistry and Chemical Technology, Večna pot 113, Ljubljana, Slovenia</p>
<p><sup>2</sup>National Institute of Biology, Večna pot 111, Ljubljana, Slovenia</p>
<p><sup>3</sup>Eawag - Swiss Federal Institute of Aquatic Science and Technology, Ueberlandstrasse 133, Duebendorf, Switzerland</p>
Open for citation & comment<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-family:"Times New Roman",serif">This AOP starts with inhibition of Fyna (Src family tyrosine kinase A) activity and leads to increased mortality (AO) via reduced eye size (microphthalmos). Inhibition of Fyna activity is defined as the molecular initiating event (MIE) that leads to reduction in Plxna2 phosphatase activity (KE1). Reduction in Plxna2 activity leads to overexpression of <em>rasl11b</em> (KE2). Increased levels of Rasl11b cause reduction of cell proliferation in the developing eye (KE3). Reduced cell proliferation in the developing eye leads to reduced eye size (KE4) which in turn leads to altered visual function (KE5). It is in some cases accompanied with severe eye deformation which can lead to increase in mortality for the individual. Fyna can be inhibited by pharmaceuticals, such as Saracatinib, Mastinib, Staurosporine and Rosmarinic acid, as has been shown in several <em>in vitro</em> studies. As Fyna kinase inhibition is being intensively studied in the fields of </span></span></span><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-family:"Times New Roman",serif">Alzheimer's disease and anti-inflammatory therapy, the use of the inhibitors has the potential to significantly increase in the following decades. The k</span></span></span><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-family:"Times New Roman",serif">ey events described in this AOP were mostly studied in Zebrafish (Danio rerio) but can be theoretically transferred to other vertebrates as the involved genes are highly similar among vertebrates. </span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-family:"Times New Roman",serif">The motivation behind building the AOP was methodological. Our team has recently developed molecular causal networks for developmental cardiotoxicity and neurotoxicity in zebrafish (</span></span></span><a href="https://doi.org/10.1021/acs.chemrestox.0c00095" title="DOI URL">doi.org/10.1021/acs.chemrestox.0c00095</a><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-family:"Times New Roman",serif">). These networks are highly curated, but rather large, going from adverse outcomes on the organ level upstream to wherever evidence takes us (many times finishing at what would be called MIEs). As there are many causal networks already present on the </span><a href="http://causalbionet.com/" style="color:#0563c1; text-decoration:underline"><span style="font-family:"Times New Roman",serif">http://causalbionet.com/</span></a><span style="font-family:"Times New Roman",serif"> (mostly for humans and for lung conditions), we were wondering how the rich knowledge available in causal pathways could be translated to AOPs. The AOP described in this document is one such example. </span></span></span></p>
<p>Evidence for perturbation of Fyna is available for rosmarinic acid (<span style="background-color:transparent; color:#000000; font-family:Calibri,sans-serif; font-size:11pt">Jelić et al., 2007), stauroporine (Kinoshita et al., 2006; Lamers et al., 2003) and AZD0530 (Green et al., 2009, Morisot et al., 2019). </span></p>
<p>Increased mortality is one of the most common regulatory assessment endpoints, along with reduced growth and reduced reproduction.</p>
<p>Maintenance of sustainable fish and wildlife populations (i.e., adequate to ensure long-term delivery of valued ecosystem services) is a widely accepted regulatory goal upon which risk assessments and risk management decisions are based.</p>
adjacentLowModerateadjacentLowLowadjacentLowHighadjacentLowHighadjacentNot SpecifiedNot SpecifiedadjacentNot SpecifiedNot SpecifiedadjacentHighHigh<table border="1" cellpadding="1" cellspacing="1" style="width:500px">
<tbody>
<tr>
<td><span style="font-family:Arial,Helvetica,sans-serif"><strong>Support for Essenti<span style="font-size:16px">ality of KEs</span></strong></span></td>
<td>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:16px"><strong>Defining Question</strong>: Are downstream KEs and/or the AO prevented if an upstream KE is blocked?</span></span></p>
<ul>
<li><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>High (Strong):</strong> Direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important KEs (e.g. stop/reversibility studies, antagonism, knock out models, etc.).</span></span></li>
<li><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Moderate:</strong> Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE leading to increase in KE down or AO.</span></span></li>
<li><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low (Weak):</strong> No or contradictory experimental evidence of the essentiality of any of the KEs.</span></span></li>
</ul>
</td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>MIE:</strong> Inhibition of Fyna</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low:</strong> No experimental evidence of essentiality. </span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KE1:</strong> Inhibition of Plxna2</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Moderate:</strong> reduced eye size phenotype can be rescued by plxna2 activation (St Clair et al., 2018).</span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KE2:</strong> Overexpression of <em>rasl11b</em></span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low:</strong> No experimental evidence of essentiality. </span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KE3:</strong> Decreased cell proliferation</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low:</strong> No experimental evidence of essentiality. </span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KE4:</strong> Decreased eye size</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low:</strong> No experimental evidence of essentiality. </span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KE5: </strong>Altered visual function</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low:</strong> No experimental evidence of essentiality. </span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>AO:</strong> Increased mortality</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>High:</strong> Inability to perceive the environment leads to increase in mortality (Dehnert et al., 2019; Besson et al., 2020).</span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>AO:</strong> Decrease of population trajectory</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>High: </strong>decrease in population trajectory is an imminent result of increased mortality (Rearick et al., 2018).</span></span></td>
</tr>
</tbody>
</table>
<p> </p>
HighDuring brain developmentHigh<p>An overall assessment of this AOP shows that there is moderate biological plausibility to support a qualitative link between the Fyna kinase inhibition to the KE5 of altered visual function and high evidence linking KE5 to decreased population trajectory. Biological plausibility is considered moderate because there is ample evidence from gain- and loss- of function experiments and knock out animal models that support the relationships between key events and are consistent with current biological knowledge. A score of high in this respect would require further evidence for chemical inhibition or experimental downregulation of zebrafish Fyna kinase and direct or more extensive evidence linking Plxna2 inhibition to <em>rasl11b</em> overexpression. The evidence for essentiality of the KEs is mostly missing therefore the overall assessment of essentiality is low. The same goes for empirical support, currently there is no evidence for empirical support. Additional studies are needed to obtain data for empirical support, therefore, the empirical support of KERs is considered is low.</p>
<p dir="ltr"><strong>Life stage:</strong> The current AOP is applicable from minutes after fertilization (0 hpf) and up to end of gastrulation phase (~10.33 hpf) (Rongish & Kinsey, 2000). After gastrulation phase Fyna kinase is not bserved in developing zebrafish and inhibition of Fyna kinase is not applicable.</p>
<p dir="ltr"><strong>Taxonomic:</strong> This AOP is based on experimental evidence from studies on zebrafish, but is potentially also relevant to other vertebrates, because of conservation of all involved key events (Fyna activation, Sema/Plxna signaling, Rasl11b, Eye development).</p>
<p><strong>Sex: </strong>Sex differences are typically not investigated in tests using early life stages of zebrafish and it is currently unclear whether sex-related differences are important in this AOP.</p>
<table border="1" cellpadding="1" cellspacing="1" style="width:500px">
<tbody>
<tr>
<td><span style="font-family:Arial,Helvetica,sans-serif"><strong>Support for Essenti<span style="font-size:16px">ality of KEs</span></strong></span></td>
<td>
<p><span style="font-family:Arial,Helvetica,sans-serif"><span style="font-size:16px"><strong>Defining Question</strong>: Are downstream KEs and/or the AO prevented if an upstream KE is blocked?</span></span></p>
<ul>
<li><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>High (Strong):</strong> Direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important KEs (e.g. stop/reversibility studies, antagonism, knock out models, etc.).</span></span></li>
<li><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Moderate:</strong> Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE leading to increase in KE down or AO.</span></span></li>
<li><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low (Weak):</strong> No or contradictory experimental evidence of the essentiality of any of the KEs.</span></span></li>
</ul>
</td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>MIE:</strong> Inhibition of Fyna</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low:</strong> No experimental evidence of essentiality. </span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KE1:</strong> Inhibition of Plxna2</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Moderate:</strong> reduced eye size phenotype can be rescued by plxna2 activation (St Clair et al., 2018).</span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KE2:</strong> Overexpression of <em>rasl11b</em></span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low:</strong> No experimental evidence of essentiality. </span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KE3:</strong> Decreased cell proliferation</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low:</strong> No experimental evidence of essentiality. </span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KE4:</strong> Decreased eye size</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low:</strong> No experimental evidence of essentiality. </span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KE5: </strong>Altered visual function</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low:</strong> No experimental evidence of essentiality. </span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>AO:</strong> Increased mortality</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>High:</strong> Inability to perceive the environment leads to increase in mortality (Dehnert et al., 2019; Besson et al., 2020).</span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>AO:</strong> Decrease of population trajectory</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>High: </strong>decrease in population trajectory is an imminent result of increased mortality (Rearick et al., 2018).</span></span></td>
</tr>
</tbody>
</table>
<p> </p>
<table border="1" cellpadding="1" cellspacing="1" style="width:500px">
<tbody>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Support for Biological Plausibility of KERs</strong></span></span></td>
<td>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Defining Question:</strong> Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge?</span></span></p>
<ul>
<li><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>High (Strong)</strong>: Extensive understanding of the KER based on extensive previous documentation and broad acceptance.</span></span></li>
<li><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Moderate</strong>: KER is plausible based on analogy to accepted biological relationships, but scientific understanding is incomplete.</span></span></li>
<li><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low (Weak)</strong>: Empirical support for association between KEs, but the structural or functional relationship between them is not understood.</span></span>
<p> </p>
</li>
</ul>
</td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KER1</strong>: Inhibition of Fyna leads to inhibition of Plxna2</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Moderate</strong>: Extensive understanding of Fyna phosphorylating activity and consequent changes in Plxna2 signalization, but there is currently no data on chemical inhibition of zebrafish Fyna kinase.</span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KER2</strong>: Inhibition of Plxna2 leads to overexpression of rasl11b</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>Low</strong>: There is missing direct evidence for the relationship and poor functional and structural understanding of interactions</span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KER3</strong>: Overexpression of rasl11b leads decreased cell proliferation</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>High</strong>: Impact of Rasl11b on cell proliferation is well understood across different taxonomic groups.</span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KER4</strong>: Decreased cell proliferation leads to decreased eye size</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>High</strong>: Extensive understanding that decreased proliferation of RPCs leads to decreased eye size.</span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KER5</strong>: Decreased eye size leads to altered Visual function</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>High</strong>: Extensive understanding that changes in eye size greatly effect visual function</span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KER6</strong>: Altered visual function leads to increased mortality</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>High</strong>: Extensive understanding that defective visual function greatly increases the chance of death due to various factors</span></span></td>
</tr>
<tr>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>KER7</strong>: Increased mortality leads to decrease of population trajectory</span></span></td>
<td><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong>High</strong>: Extensive understanding that increased mortality on individual level decreases population trajectory</span></span></td>
</tr>
</tbody>
</table>
<p><strong>Empirical support:</strong> Currently there is no sufficient evidence to estimate the weight of the evidence of empirical support for KERs in this AOP. Further more specific research on the relationships between the entities involved in the AOP is needed.</p>
<p> </p>
<p>Data to support the quantitative understanding of this AOP is currently lacking.</p>
ModerateModerateModerate<p dir="ltr">Babkiewicz, E., Bazała, M., Urban, P., Maszczyk, P., Markowska, M., & Maciej Gliwicz, Z. (2020). The effects of temperature on the proxies of visual detection of Danio rerio larvae: observations from the optic tectum. https://doi.org/10.1242/bio.047779</p>
<p dir="ltr">Besson, M., Feeney, W. E., Moniz, I., François, L., Brooker, R. M., Holzer, G., Metian, M., Roux, N., Laudet, V., & Lecchini, D. (n.d.). Anthropogenic stressors impact fish sensory development and survival via thyroid disruption. https://doi.org/10.1038/s41467-020-17450-8</p>
<p dir="ltr">Challa, A. K., & Chatti, K. (2013). Conservation and Early Expression of Zebrafish Tyrosine Kinases Support the Utility of Zebrafish as a Model for Tyrosine Kinase Biology. 10(3). https://doi.org/10.1089/zeb.2012.0781</p>
<p dir="ltr">Corral-López, A., Garate-Olaizola, M., Buechel, S. D., Kolm, N., & Kotrschal, A. (2017). On the role of body size, brain size, and eye size in visual acuity. Behavioral Ecology and Sociobiology, 71(12). https://doi.org/10.1007/s00265-017-2408-z</p>
<p dir="ltr">Dehnert, G. K., Karasov, W. H., & Wolman, M. A. (2019). 2,4-Dichlorophenoxyacetic acid containing herbicide impairs essential visually guided behaviors of larval fish. Aquatic Toxicology, 209(October 2018), 1–12. https://doi.org/10.1016/j.aquatox.2019.01.015</p>
<p dir="ltr">Emerson, S. E., St. Clair, R. M., Waldron, A. L., Bruno, S. R., Duong, A., Driscoll, H. E., Ballif, B. A., McFarlane, S., & Ebert, A. M. (2017). Identification of target genes downstream of semaphorin6A/PlexinA2 signaling in zebrafish. Developmental Dynamics, 246(7), 539–549. https://doi.org/10.1002/dvdy.24512</p>
<p dir="ltr">Franco, M., & Luca Tamagnone, &. (2008). Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive. EMBO Reports, 9, 865–871. https://doi.org/10.1038/embor.2008.139</p>
<p dir="ltr">Green, T. P., Fennell, M., Whittaker, R., Curwen, J., Jacobs, V., Allen, J., Logie, A., Hargreaves, J., Hickinson, D. M., Wilkinson, R. W., Elvin, P., Boyer, B., Carragher, N., Plé, P. A., Bermingham, A., Holdgate, G. A., Ward, W. H. J., Hennequin, L. F., Davies, B. R., & Costello, G. F. (2009). Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. Molecular Oncology, 3(3), 248–261. https://doi.org/10.1016/j.molonc.2009.01.002</p>
<p dir="ltr">He, H., Dai, J., Zhuo, R., Zhao, J., Wang, H., Sun, F., Zhu, Y., & Xu, D. (2018). Study on the mechanism behind lncRNA MEG3 affecting clear cell renal cell carcinoma by regulating miR-7/RASL11B signaling. Journal of Cellular Physiology, 233(12), 9503–9515. https://doi.org/10.1002/jcp.26849</p>
<p dir="ltr">Kennedy, B. N., Stearns, G. W., Smyth, V. A., Ramamurthy, V., Van Eeden, F., Ankoudinova, I., Raible, D., Hurley, J. B., & Brockerhoff, S. E. (2004). Zebrafish rx3 and mab21l2 are required during eye morphogenesis. Developmental Biology, 270(2), 336–349. https://doi.org/10.1016/j.ydbio.2004.02.026</p>
<p dir="ltr">Le, H. G., Dowling, J. E., & Cameron, D. J. (2012). Early retinoic acid deprivation in developing zebrafish results in microphthalmia. Visual Neuroscience, 29(4–5), 219–228. https://doi.org/10.1017/S0952523812000296</p>
<p dir="ltr">Nygaard, H. B., Van Dyck, C. H., & Strittmatter, S. M. (2014). Fyn kinase inhibition as a novel therapy for Alzheimer’s disease. Alzheimer’s Research and Therapy, 6(1), 1–8. https://doi.org/10.1186/alzrt238</p>
<p dir="ltr">Rongish BJ, Kinsey WH. Transient nuclear localization of Fyn kinase during development in zebrafish. Anat Rec. 2000 Oct 1;260(2):115-23. doi: 10.1002/1097-0185(20001001)260:2<115::AID-AR10>3.0.CO;2-C. PMID: 10993948.</p>
<p>Sasaki, Y., Cheng, C., Uchida, Y., Nakajima, O., Ohshima, T., Yagi, T., Taniguchi, M., Nakayama, T., Kishida, R., Kudo, Y., Ohno, S., Nakamura, F., & Goshima, Y. (2002). Fyn and Cdk5 Mediate Semaphorin-3A Signaling, Which Is Involved in Regulation of Dendrite Orientation in Cerebral Cortex drite guidance in the cerebral cortex. We propose a signal transduction pathway in which Fyn and Cdk5 mediate neuronal guidance regula. Neuron, 35, 907–920.</p>
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