Decreased, ALDH1A (RALDH) enzyme activity

97-77-8

AUZONCFQVSMFAP-UHFFFAOYSA-N

Tetraethylthiuram disulfide

Tetraethylthiuram disulfide Thioperoxydicarbonic diamide, ([(H2N)C(S)]2S2), tetraethyl- 1,1'-Dithiobis(N,N-diethylthioformamide) Abstensil Abstinil Abstinyl Accel TET Accel TET-R Akrochem TETD Alcophobin Antabus Antabuse Antadix Antaethyl Antalcol Antetan Antetil Anticol Antietanol Antietil Antikol Antivitium Aversan Averzan Bis(diethylthiocarbamoyl) disulfide Bis(N,N-diethylthiocarbamoyl) disulfide bis-(N,N-Diethylthiocarbamoyl)disulfide Contralin Cronetal Dicupral Disulfide, bis(diethylthiocarbamoyl) Disulfirame disulfiramo Ekagom DTET Ekagom TEDS Ekagom TETDS Espenal Esperal Ethyl Thiram Ethyl Thiurad Ethyl Tuads Ethyl Tuex Exhoran Exhorran Krotenal N,N,N',N'-Tetraethylthiuram disulfide Nocceler TED Nocceler TET Nocceler TET-G NSC 25953 Refusal Sanceler TET Sanceler TET-G Soxinol TET Stopetyl Tetradin Tetradine Tetraethyldithiuram disulfide Tetraethylthioperoxydicarbonic diamide Tetraethylthiram disulfide Tetraethylthiuram Tetraethylthiuram sulfide Tetraethylthiuramdisulfide Tetraetil Teturam Teturamin Thioperoxydicarbonic diamide ([(H2N)C(S)]2S2), N,N,N',N'-tetraethyl- THIOPEROXYDICARBONIC DIAMIDE, TETRAETHYL- Thiuram E Thiuranide Thioperoxydicarbonic diamide ([(H2N)C(S)]2S2), tetraethyl-

DTXSID1021322

1836-75-5

XITQUSLLOSKDTB-UHFFFAOYSA-N

Nitrofen

Benzene, 2,4-dichloro-1-(4-nitrophenoxy)- 2,4-Dichloro-1-(4-nitrophenoxy)benzene 2',4'-Dichloro-4-nitrodiphenyl ether 2,4-Dichloro-4'-nitrodiphenyl ether 2,4-Dichlorophenyl 4-nitrophenyl ether 2,4-Dichlorophenyl p-nitrophenyl ether 2,4-Dichlorophenyl-4'-nitrophenylether 4-(2,4-Dichlorophenoxy)nitrobenzene 4'-Nitro-2,4-dichlorodiphenyl ether 4-Nitro-2',4'-dichlorophenyl ether Ether, 2,4-dichlorophenyl p-nitrophenyl Mezotox Niclofen Nitrochlor Nitrofen [benzene, 2,4-dichloro-1-(4-nitrophenoxy)-] nitrofene Preparation 125 Trizilin Trizilin 25

DTXSID7020970

64-17-5

LFQSCWFLJHTTHZ-UHFFFAOYSA-N

Ethanol

Ethyl 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

DTXSID9020584

17804-35-2

RIOXQFHNBCKOKP-UHFFFAOYSA-N

Benomyl

Benomyl (Methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate) Carbamic acid, [1-[(butylamino)carbonyl]-1H-benzimidazol-2-yl]-, methyl ester [1-[(Butylamino)carbonyl]-1H-benzimidazol-2-yl]carbamic acid methyl ester 2-Benzimidazolecarbamic acid, 1-(butylcarbamoyl)-, methyl ester Agrocit Benlate Benlate 50W Benomil benomilo Benomyl-Imex Carbamic acid, (1-(butylamino)carbonyl)-1H-benzimidazol-2-yl), methyl ester Carbamic acid, N-[1-[(butylamino)carbonyl]-1H-benzimidazol-2-yl]-, methyl ester Du Pont 1991 Fundazol Fundazol 50WP Fungicide D-1991 Fungochrom Kribenomyl Methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate Methyl 1-(butylcarbamoyl)-2-benzimidazolylcarbamate Methyl 1-(butylcarbamoyl)benzimidazol-2-ylcarbamate NSC 263489 Tersan 1991 Zetamil

DTXSID5023900

87009-57-2

XZMCDFZZKTWFGF-VMIGTVKRSA-N

(~13~C,~15~N_2_)Cyanamide

DTXSID90745933

486-66-8

ZQSIJRDFPHDXIC-UHFFFAOYSA-N

7,4'-Dihydroxyisoflavone

4',7-Dihydroxyisoflavone 4H-1-Benzopyran-4-one, 7-hydroxy-3-(4-hydroxyphenyl)- 7,4'-Dihydroxyisoflavone 7-hidroxi-3-(4-hidroxifenil)-4-benzopirona 7-Hydroxy-3-(4-hydroxyphenyl)-4-benzopyron 7-hydroxy-3-(4-hydroxyphenyl)-4-benzopyrone 7-Hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one Daidzeol Isoaurostatin Isoflavone, 4',7-dihydroxy-

DTXSID9022310

2212-67-1

DEDOPGXGGQYYMW-UHFFFAOYSA-N

Molinate

1H-Azepine-1-carbothioic acid, hexahydro-, S-ethyl ester Ethyl 1-hexamethyleneiminecarbothiolate Hexahydro-1H-azepin-1-carbothioic acid S-ethyl ester Molinat molinato S-Ethyl hexahydro-1H-azepine-1-carbothioate S-Ethyl hexahydroazepine-1-carbothioate S-Ethyl N,N-hexamethylenethiocarbamate Stauffer R 4572

DTXSID6024206

1114-71-2

SGEJQUSYQTVSIU-UHFFFAOYSA-N

Pebulate

Propyl N-ethyl-N-butylthiocarbamate

DTXSID8021199

1929-77-7

OKUGPJPKMAEJOE-UHFFFAOYSA-N

Vernolate

Vernam

DTXSID7024376

2008-41-5

BMTAFVWTTFSTOG-UHFFFAOYSA-N

Butylate

DTXSID7023936

2303-17-5

MWBPRDONLNQCFV-UHFFFAOYSA-N

Tri-allate

Triallate Carbamothioic acid, bis(1-methylethyl)-, S-(2,3,3-trichloro-2-propenyl) ester 2,3,3-Trichloroallyl N,N-diisopropylthiocarbamate Avadex BW Carbamic acid, diisopropylthio-, S-(2,3,3-trichloroallyl) ester Carbamothioic acid, N,N-bis(1-methylethyl)-, S-(2,3,3-trichloro-2-propen-1-yl) ester Dipthal NSC 379698 S-(2,3,3-Trichloro-2-propenyl) bis(1-methylethyl)carbamothioate S-(2,3,3-Trichloroallyl) diisopropylthiocarbamate S-2,3,3-Trichloroallyl diisopropylthiocarbamate S-2,3,3-Trichloroallyl N,N-diisopropylthiocarbamate trialato Triallat Triamyl Trillate

DTXSID5024344

1134-23-2

DFCAFRGABIXSDS-UHFFFAOYSA-N

Cycloate

Ethyl cyclohexylethylthiocarbamate

DTXSID6032356

PR:000003920

PR retinal dehydrogenase 1

CHEBI:15367

CHEBI all-trans-retinoic acid

GO:0002138

GO retinoic acid biosynthetic process

WIKI decreased

4-diethylaminobenzaldehyde (DEAB)

2022-02-15T10:55:04

Disulfiram

2017-08-03T10:53:21

WIN18466

2022-02-15T10:56:00

nitrofen

2019-05-22T05:18:44

Ethanol

2018-04-05T06:38:48

All-trans retionic acid

2022-02-15T11:14:00

Bisdiamine

2019-05-22T05:19:08

Vitamin A

2022-02-15T11:15:48

BMS-89453

2022-02-15T10:46:31

Benomyl

2016-11-29T18:42:27

WIN18,466

2021-10-30T06:33:51

(~13~C,~15~N_2_)Cyanamide

2021-10-30T07:14:10

Daidzein

2016-11-29T18:42:26

Molinate

2021-10-30T07:14:59

Pebulate

2021-10-30T07:15:21

Vernolate

2021-10-30T07:15:49

Butylate

2021-10-30T07:18:12

Tri-allate

2021-10-30T07:19:13

Cycloate

2021-10-30T07:19:37

Diethylaminobenzaldehyde

2019-05-22T05:17:55

All-trans retinoic acid

2022-02-15T10:43:46

WIN18446

2022-02-15T10:47:00

WCS_9606

common toxicological species human

10090

NCBI mouse

10116

NCBI rat

WikiUser_28

Vertebrates

WCS_9031

common ecological species chicken

WCS_7955

common ecological species zebrafish

Decreased, ALDH1A (RALDH) enzyme activity

Decreased, ALDH1A activity

Molecular

The oxidation of retinal to all-trans retinoic acid (atRA) is an irreversible reaction carried out by retinaldehyde dehydrogenases ALDH1A1, ALDH1A2, ALDH1A3 (RALDH1, RALDH2, RALDH3). ALDH1A2 is responsible for the second step of the metabolism of vitamin A into atRA (<a href="#_ENREF_4" title="Chatzi, 2013 #14">Chatzi et al, 2013</a>; <a href="#_ENREF_16" title="Shannon, 2017 #15">Shannon et al, 2017</a>).The role of that reaction is to maintain atRA concentrations, with ALDH1A2 being most active during early development (<a href="#_ENREF_8" title="Koppaka, 2012 #16">Koppaka et al, 2012</a>; <a href="#_ENREF_16" title="Shannon, 2017 #15">Shannon et al, 2017</a>). Raldh2-deficient mice exhibit severe developmental defects due to loss of atRA, but the phenotype is rescued by administration of exogenous RA (<a href="#_ENREF_11" title="Niederreither, 1999 #19">Niederreither et al, 1999</a>). Thus, ALDH1A2 activity is essential for atRA-dependent developmental processes.

There are no OECD validated assays for measuring ALDH1A2 inhibition. ALDH1A2 mRNA and protein levels can be measured using various probes, antibodies as well as ELISA kits that are commercially available. Enzyme activity can be assessed in assays including measurement of atRA formation (<a href="#_ENREF_2" title="Arnold, 2015 #50">Arnold et al, 2015</a>) or NADH formation (<a href="#_ENREF_7" title="Harper, 2018 #51">Harper et al, 2018</a>; <a href="#_ENREF_15" title="Schindler, 1998 #52">Schindler et al, 1998</a>) and several ALDH activity assay kits using different approaches are commercially available; e.g. AldeflourTM kit (<a href="#_ENREF_6" title="Flahaut, 2016 #53">Flahaut et al, 2016</a>).

The retinoid signaling system is highly conserved across distant animal species (<a href="#_ENREF_3" title="Bushue, 2010 #30">Bushue & Wan, 2010</a>; <a href="#_ENREF_14" title="Rhinn, 2012 #31">Rhinn & Dollé, 2012</a>).

CL:0000255

CL eukaryotic cell

High Male High Female

High

All life stages

Moderate High Moderate

<a name="_ENREF_1">Allen EMG, Anderson DGR, Florang VR, Khanna M, Hurley TD, Doorn JA (2010) Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: implications for the mechanism of enzyme inhibition. Chem Res Toxicol 23: 1843-1850</a> <a name="_ENREF_2">Arnold SL, Kent T, Hogarth CA, Schlatt S, Prasad B, Haenisch M, T. W, Muller CH, Griswold MD, Amory JK, Isoherranen N (2015) Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations. J Lipid Res 56: 342-357</a> <a name="_ENREF_3">Bushue N, Wan YJY (2010) Retinoid pathway and cancer therapeutics. Adv Drug Deliv Rev 62: 1285-1298</a> <a name="_ENREF_4">Chatzi C, Cunningham TJ, Duester G (2013) Investigation of retinoic acid function during embryonic brain development using retinaldehyde-rescued Rdh10 knockout mice. Dev Dyn 242: 1056-1065</a> <a name="_ENREF_5">Chen Y, Zhu JY, Hong KH, Mikles DC, Georg GI, Goldstein AS, Amory JK, Schönbrunn E (2018) Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors. ACS Chem Biol 13: 582-590</a> <a name="_ENREF_6">Flahaut M, Jauquier N, Nardou K, Bourloud KB, Joseph JM, Barras D, Widmann C, Gross N, Renella R, Mühlethaler-Mottet A (2016) Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma. BMC Cancer 16: 781</a> <a name="_ENREF_7">Harper AR, Le AT, Mather T, Burgett A, Berry W, Summers JA (2018) Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes. Bioorg Med Chem 26: 5766-5779</a> <a name="_ENREF_8">Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, Petersen D, Deitrich RA, Hurley TD, Vasilio V (2012) Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol Rev 64: 520-539</a> <a name="_ENREF_9">Lowe ED, Gao GY, Johnson LN, Keung WM (2008) Structure of daidzin, a naturally occurring anti-alcohol-addiction agent, in complex with human mitochondrial aldehyde dehydrogenase. J Med Chem 51: 4482-4487</a> <a name="_ENREF_10">Nagasawa HT, DeMaster EG, Redfern B, Shirota FN, Goon DJ (1990) Evidence for nitroxyl in the catalase-mediated bioactivation of the alcohol deterrent agent cyanamide. J Med Chem 33: 3120-3122</a> <a name="_ENREF_11">Niederreither K, Subbarayan V, Dollé P, Chambon P (1999) Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 21: 444-448</a> <a name="_ENREF_12">Paik J, Haenisch M, Muller CH, Goldstein AS, Arnold S, Isoherranen N, Brabb T, Treuting PM, Amory JK (2014) Inhibition of retinoic acid biosynthesis by the bisdichloroacetyldiamine WIN 18,446 markedly suppresses spermatogenesis and alters retinoid metabolism in mice. J Biol Chem 289: 15104-15117</a> <a name="_ENREF_13">Quistad GB, Sparks SE, Casida JE (1994) Aldehyde dehydrogenase of mice inhibited by thiocarbamate herbicides. Life Sci 55: 1537-1544</a> <a name="_ENREF_14">Rhinn M, Dollé P (2012) Retinoic acid signalling during development. Development 139: 843-858</a> <a name="_ENREF_15">Schindler JF, Berst KB, Plapp BV (1998) Inhibition of human alcohol dehydrogenases by formamides. J Med Chem 41: 1696-1701</a> <a name="_ENREF_16">Shannon SR, Moise AR, Trainor PA (2017) New insights and changing paradigms in the regulation of vitamin A metabolism in development. Wiley Interdiscip Rev Dev Biol 6: 10.1002/wdev.1264</a> <a name="_ENREF_17">Shirota FN, DeMaster EG, Nagasawa HT (1987) Cyanide is a product of the catalase-mediated oxidation of the alcohol deterrent agent, cyanamide. Toxicol Lett 37: 7-12</a> <a name="_ENREF_18">Staub RE, Quistad GB, Casida JE (1998) Mechanism for benomyl action as a mitochondrial aldehyde dehydrogenase inhibitor in mice. Chem Res Toxicol 11: 535-543</a> AOPWiki 2021-05-24T10:56:46

2024-12-17T12:04:12

Decreased, all-trans retinoic acid (atRA) concentration

Decreased, atRA concentration

Tissue

All-trans retinoic acid (atRA) is the active form of vitamin A/all-trans retinol and is involved in regulating a large number of developmental processes (<a href="#_ENREF_2" title="Bushue, 2010 #4185">Bushue & Wan, 2010a</a>; <a href="#_ENREF_9" title="Ghyselinck, 2019 #4198">Ghyselinck & Duester, 2019</a>). Although 9-cis RA and 13-cis RA are other metabolic derivatives of vitamin A, atRA is generally considered the primary active metabolite during development, mainly acting as a short-range paracrine signaling molecule (<a href="#_ENREF_7" title="Cunningham, 2015 #4190">Cunningham & Duester, 2015</a>). atRA exerts dose-dependent effects on morphogenesis, so disruption to atRA concentrations during development can lead to malformations in numerous tissues and organs. During development the spatiotemporal regulation of atRA concentrations in target tissues is tightly controlled by a balance of synthesis and degradation enzymes (<a href="#_ENREF_13" title="Kedishvili, 2013 #4209">Kedishvili, 2013</a>). Cellular atRA synthesis starts by oxidation of vitamin A to retinaldehyde (RAL) by retinol dehydrogenase-10 (RDH10). RAL is then irreversibly converted to atRA by RAL dehydrogenases (ALDH1A1, ALD1A2, or ALDH1A3). To maintain appropriate retinoid levels in tissues, RAL can be converted back to retinol by enzymatic reactions; further retinoid levels can be controlled by enzymatic degradation of atRA by the cytochrome P450 enzymes CYP26A1, CYP26B1, or CYP26C1, which are differentially expressed throughout the mammalian body (<a href="#_ENREF_12" title="Isoherranen, 2019 #4205">Isoherranen & Zhong, 2019</a>; <a href="#_ENREF_19" title="Shimozono, 2013 #4243">Shimozono et al, 2013</a>). Inhibition/disruption of any of the enzymes of the atRA synthesis pathway, or increased expression of the atRA degradation enzymes can lead to decreased concentrations of atRA in target cells (<a href="#_ENREF_13" title="Kedishvili, 2013 #4209">Kedishvili, 2013</a>). The atRA functions as a ligand for the nuclear retinoic acid receptors (RARs), which form heterodimers with the retinoid X receptors (RXRs); the atRA:RAR:RXR complex then binds to retinoic acid response elements (RAREs) upstream of target genes, leading to activation or repression of gene expression in target cells (<a href="#_ENREF_5" title="Chambon, 1996 #4187">Chambon, 1996</a>; <a href="#_ENREF_15" title="le Maire, 2019 #4217">le Maire et al, 2019</a>). The type and number of RAR/RXRs differ between evolutionary distant animals, but functionally they are all involved in the regulation of development (<a href="#_ENREF_11" title="Gutierrez-Mazariegos, 2014 #4201">Gutierrez-Mazariegos et al, 2014</a>).

Direct measurements of atRA in serum (humans, animals) can be performed by various chromatographic methods (<a href="#_ENREF_10" title="Gundersen, 2006 #4200">Gundersen, 2006</a>), including high performance liquid chromatography (HPLC) or liquid chromatography-tandem mass spectrometry (LC-MS) (<a href="#_ENREF_16" title="Morgenstern, 2021 #4228">Morgenstern et al, 2021</a>). Indirect measurements in cells and animal models can be performed with reporter assays utilizing RAR-RXR-RARE or RXR-RXR-RARE promoter elements, which are activated by atRA, driving expression of reporter proteins. These reporter assays can detect the presence of atRA in tissues in a semi-quantitative manner. Examples include reporter mouse lines (<a href="#_ENREF_4" title="Carlsen, 2021 #4186">Carlsen et al, 2021</a>; <a href="#_ENREF_18" title="Rossant, 1991 #547">Rossant et al, 1991</a>; <a href="#_ENREF_20" title="Solomin, 1998 #4247">Solomin et al, 1998</a>), reporter cell lines (<a href="#_ENREF_21" title="Wagner, 1992 #1240">Wagner et al, 1992</a>) and transient transfection of constructs for in vitro cell-based assays (<a href="#_ENREF_6" title="Chassot, 2020 #4188">Chassot et al, 2020</a>).

The retinoid signaling system is highly conserved across animal species (<a href="#_ENREF_3" title="Bushue, 2010 #30">Bushue & Wan, 2010b</a>; <a href="#_ENREF_17" title="Rhinn, 2012 #31">Rhinn & Dollé, 2012</a>). atRA acts as a ligand for the nuclear retinoic acid (RAR) receptors, which upon activation regulate gene transcription in target cells. The type and number of RARs differ between evolutionary distant animals, but functionally they are all involved in the regulation of development.

High Male High Female

Moderate

All life stages

High High High Moderate

<a name="_ENREF_1">Arnold SLM, Kent T, Hogarth CA, Griswold MD, Amory JK, Isoherranen N (2015) Pharmacological inhibition of ALDH1A in mice decreases all-trans retinoic acid concentrations in a tissue specific manner. Biochem Pharmacol 95: 177-192</a> <a name="_ENREF_2">Bushue N, Wan YJ (2010a) Retinoid pathway and cancer therapeutics. Adv Drug Deliv Rev 62: 1285-1298</a> <a name="_ENREF_3">Bushue N, Wan YJY (2010b) Retinoid pathway and cancer therapeutics. Adv Drug Deliv Rev 62: 1285-1298</a> <a name="_ENREF_4">Carlsen H, Ebihara K, Kuwata NH, Kuwata K, Aydemir G, Ruhl R, Blomhoff R (2021) A transgenic reporter mouse model for in vivo assessment of retinoic acid receptor transcriptional activation. Int J Vitam Nutr Res: 1-13</a> <a name="_ENREF_5">Chambon P (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10: 940-954</a> <a name="_ENREF_6">Chassot AA, Le Rolle M, Jolivet G, Stevant I, Guigonis JM, Da Silva F, Nef S, Pailhoux E, Schedl A, Ghyselinck NB, Chaboissier MC (2020) Retinoic acid synthesis by ALDH1A proteins is dispensable for meiosis initiation in the mouse fetal ovary. Sci Adv 6: eaaz1261</a> <a name="_ENREF_7">Cunningham TJ, Duester G (2015) Mechanisms of retinoic acid signalling and its roles in organ and limb development. Nat Rev Mol Cell Biol 16: 110-123</a> <a name="_ENREF_8">Deltour L, Ang HL, Duester G (1996) Ethanol inhibition of retinoic acid synthesis as a potential mechanism for fetal alcohol syndrome. FASEB J 10: 1050-1057</a> <a name="_ENREF_9">Ghyselinck NB, Duester G (2019) Retinoic acid signaling pathways. Development 146</a> <a name="_ENREF_10">Gundersen TE (2006) Methods for detecting and identifying retinoids in tissue. J Neurobiol 66: 631-644</a> <a name="_ENREF_11">Gutierrez-Mazariegos J, Schubert M, Laudet V (2014) Evolution of retinoic acid receptors and retinoic acid signaling. Subcell Biochem 70: 55-73</a> <a name="_ENREF_12">Isoherranen N, Zhong G (2019) Biochemical and physiological importance of the CYP26 retinoic acid hydroxylases. Pharmacol Ther 204: 107400</a> <a name="_ENREF_13">Kedishvili NY (2013) Enzymology of retinoic acid biosynthesis and degradation. J Lipid Res 54: 1744-1760</a> <a name="_ENREF_14">Le HGT, Dowling JE, Cameron DJ (2012) Early retinoic acid deprivation in developing zebrafish results in microphthalmia. Vis Neurosci 29: 219-228</a> <a name="_ENREF_15">le Maire A, Teyssier C, Balaguer P, Bourguet W, Germain P (2019) Regulation of RXR-RAR Heterodimers by RXR- and RAR-Specific Ligands and Their Combinations. Cells 8</a> <a name="_ENREF_16">Morgenstern J, Fleming T, Kliemank E, Brune M, Nawroth P, Fischer A (2021) Quantification of All-Trans Retinoic Acid by Liquid Chromatography-Tandem Mass Spectrometry and Association with Lipid Profile in Patients with Type 2 Diabetes. Metabolites 11</a> <a name="_ENREF_17">Rhinn M, Dollé P (2012) Retinoic acid signalling during development. Development 139: 843-858</a> <a name="_ENREF_18">Rossant J, Zirngibl R, Cado D, Shago M, Giguere V (1991) Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis. Genes Dev 5: 1333-1344</a> <a name="_ENREF_19">Shimozono S, Iimura T, Kitaguchi T, Higashijima S, Miyawaki A (2013) Visualization of an endogenous retinoic acid gradient across embryonic development. Nature 496: 363-366</a> <a name="_ENREF_20">Solomin L, Johansson CB, Zetterstrom RH, Bissonnette RP, Heyman RA, Olson L, Lendahl U, Frisen J, Perlmann T (1998) Retinoid-X receptor signalling in the developing spinal cord. Nature 395: 398-402</a> <a name="_ENREF_21">Wagner M, Han B, Jessell TM (1992) Regional differences in retinoid release from embryonic neural tissue detected by an in vitro reporter assay. Development 116: 55-66</a> AOPWiki 2021-05-24T11:01:41

2023-02-13T08:04:49

Disruption, Progenitor cells of second heart field

Cellular

The first heart field (FHF) and second heart field (SHF) can be distinguished in the cardiac crescent and reside in a horseshoe shaped form (Brade et al., 2018). The SHF cells will stay in a proliferative state until they enter the heart tube to differentiate (Brade et al., 2018). The SHF promotes heart tube elongation at the venous and arterial poles and contributes to the sub pulmonary myocardium (el Robrini et al., 2016; S. Wang & Moise, 2019). The SHF will contribute to the right ventricle and outflow tract (Carlson, 2018). The SHF progenitors facilitate development of the outflow tract, atrium and right ventricle (S. Wang & Moise, 2019). The SHF contributes to the distal myocardium of the OFT and the mesodermal part of great vessel smooth muscles (Buckingham et al., 2005; Choudhary et al., 2009; Dyer & Kirby, 2009). The anterior heart field (AHF) within the SHF gives rise to the OFT and the right ventricle (Kelly et al., 2001; Meilhac et al., 2004; Zaffran et al., 2004). Mef2c positive cells are specific to the AHF (Dodou et al., 2004; Verzi et al., 2005). The AHF requires hedgehog (Hh) signaling from the pharyngeal endoderm for OFT septation but not for OFT elongation (Goddeeris et al., 2007).

Brade, T., Pane, L. S., Moretti, A., Chien, K. R., & Laugwitz, K.-L. (2018). Embryonic Heart Progenitors and Cardiogenesis. 1–18. https://doi.org/10.1101/cshperspect.a013847 Buckingham, M., Meilhac, S., & Zaffran, S. (2005). Building the mammalian heart from two sources of myocardial cells. Nature Reviews. Genetics, 6(11), 826–835. https://doi.org/10.1038/NRG1710 Carlson, B. M. (2018). Human Embryology and Developmental biology E-book. https://books.google.com/books?hl=nl&lr=&id=iyx6DwAAQBAJ&oi=fnd&pg=PP1&dq=carlson+human+embryology&ots=ZCgJJZr-17&sig=LXSoOfaYSNJLoFYaiiJHeqrNyw4 Choudhary, B., Zhou, J., Li, P., Thomas, S., Kaartinen, V., & Sucov, H. M. (2009). Absence of TGFbeta signaling in embryonic vascular smooth muscle leads to reduced lysyl oxidase expression, impaired elastogenesis, and aneurysm. Genesis (New York, N.Y. : 2000), 47(2), 115–121. https://doi.org/10.1002/DVG.20466 Dodou, E., Verzi, M. P., Anderson, J. P., Xu, S. M., & Black, B. L. (2004). Mef2c is a direct transcriptional target of ISL1 and GATA factors in the anterior heart field during mouse embryonic development. Development (Cambridge, England), 131(16), 3931–3942. https://doi.org/10.1242/DEV.01256 Dyer, L. A., & Kirby, M. L. (2009). The role of secondary heart field in cardiac development. Developmental Biology, 336(2), 137–144. https://doi.org/10.1016/J.YDBIO.2009.10.009 el Robrini, N., Etchevers, H. C., Ryckebüsch, L., Faure, E., Eudes, N., Niederreither, K., Zaffran, S., & Bertrand, N. (2016). Cardiac outflow morphogenesis depends on effects of retinoic acid signaling on multiple cell lineages. Developmental Dynamics, 245(3), 388–401. https://doi.org/10.1002/dvdy.24357 Goddeeris, M. M., Schwartz, R., Klingensmith, J., & Meyers, E. N. (2007). Independent requirements for Hedgehog signaling by both the anterior heart field and neural crest cells for outflow tract development. Development (Cambridge, England), 134(8), 1593–1604. https://doi.org/10.1242/DEV.02824 Kelly, R. G., Brown, N. A., & Buckingham, M. E. (2001). The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm. Developmental Cell, 1(3), 435–440. https://doi.org/10.1016/S1534-5807(01)00040-5 Meilhac, S. M., Esner, M., Kelly, R. G., Nicolas, J. F., & Buckingham, M. E. (2004). The clonal origin of myocardial cells in different regions of the embryonic mouse heart. Developmental Cell, 6(5), 685–698. https://doi.org/10.1016/S1534-5807(04)00133-9 Verzi, M. P., McCulley, D. J., de Val, S., Dodou, E., & Black, B. L. (2005). The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field. Developmental Biology, 287(1), 134–145. https://doi.org/10.1016/J.YDBIO.2005.08.041 Wang, S., & Moise, A. R. (2019). Recent insights on the role and regulation of retinoic acid signaling during epicardial development. Genesis, 57(7). https://doi.org/10.1002/dvg.23303 Zaffran, S., Kelly, R. G., Meilhac, S. M., Buckingham, M. E., & Brown, N. A. (2004). Right ventricular myocardium derives from the anterior heart field. Circulation Research, 95(3), 261–268. https://doi.org/10.1161/01.RES.0000136815.73623.BE AOPWiki 2019-08-13T00:51:42

2022-02-15T10:39:17

Neural crest cell migration, reduced

Reduced neural crest cell migration

Cellular

Neural crest cell (NCC) migration is dependent on coordinated expressional alterations of a large number of genes, such as integrins, matrix metalloproteinases, and cytoskeletal components. The differential regulation of a panel of such genes, has been investigated in an in vitro system, which found that histone deacetylases VPA, TSA, and SAHA exerted similar gene regulatory profiles which were quite distinct from those of other compounds shown to affect NCC migration in a scratch assay (Dreser et al., 2015). A similar experimental setup has applied a broader Affymetrix chip approach to identify biomarkers specific to the inhibition of NCC migration (Pallocca et al., 2016). In vivo evidence for the importance of specific HDACs to NCC migration has been provided by genetic knock down experiments in zebrafish embryos (DeLaurier et al., 2012). It is likely that the NCC migratory inhibition exerted by HDAC inhibitors is, at least in part, due to the broad transcriptomic impact of HDAC action on histones. However, it cannot be excluded HDAC inhibition could, to some degree, be effects altered acetylation patterns on other proteins, e.g. tubulin acetylation has been shown to be affected by HDAC activity (Hubbert et al., 2002).

NCC migration can be assessed in vitro by scratch assays, and in vivo in developing zebrafish embryos by confocal microscopy with the sox10 fluorescent reporter fishline. Sox10 is a recognized marker of migratory NCCs (Britsch et al., 2001).

Britsch, S., Goerich, D.E., Riethmacher, D., Peirano, R.I., Rossner, M., Nave, K.A., et al. (2001), Genes Dev 15: 66–78. DeLaurier, A., Nakamura, Y., Braasch, I., Khanna, V., Kato, H., Wakitani, S., et al. (2012), BMC Dev Biol 12: 16. Dreser, N., Zimmer, B., Dietz, C., Sügis, E., Pallocca, G., Nyffeler, J., et al. (2015), Neurotoxicology 50: 56–70. Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., et al. (2002), Nature 417: 455–458. Pallocca, G., Grinberg, M., Henry, M., Frickey, T., Hengstler, J.G., Waldmann, T., et al. (2016), Arch Toxicol 90: 159–180.   AOPWiki 2018-12-20T03:49:22

2018-12-20T04:10:02

transposition of the great arteries

Transposition of the great arteries

Organ

The pharyngeal arches include the pharyngeal arteries, which are responsible for correct vascular development. There are six pharyngeal arteries from which the third, fourth and sixth artery will become part of the great vessels. The third pharyngeal arteries become the carotid artery, The right fourth artery becomes the proximal part of the subclavian artery, while the left fourth pharyngeal artery will form the aortic arch. The right sixth pharyngeal artery will form the proximal part of the pulmonary arteries and the left artery will become the ductus arteriosus. Stressors related to this AO showed relationships to the ATRA pathway. Vitamin A deficiency in embryos results in heart developmental defects such as septal defects, abnormalities to the inflow and outflow tract, aortic arch abnormalities and coronary malformations in quail and rat (Dersch & Zile, 1993; Heine et al., 1985; Wilson & Warkany, 1949, 1950).

Cipollone, D., Amati, F., Carsetti, R., Placidi, S., Biancolella, M., D’Amati, G., Novelli, G., Siracusa, G., & Marino, B. (2006). A multiple retinoic acid antagonist induces conotruncal anomalies, including transposition of the great arteries, in mice. Cardiovascular Pathology : The Official Journal of the Society for Cardiovascular Pathology, 15(4), 194–202. https://doi.org/10.1016/J.CARPATH.2006.04.004 Dersch, H., & Zile, M. H. (1993). Induction of normal cardiovascular development in the vitamin A-deprived quail embryo by natural retinoids. Developmental Biology, 160(2), 424–433. https://doi.org/10.1006/dbio.1993.1318 Fujino, H., Nakagawa, M., Nishijima, S., Okamoto, N., Hanato, T., Watanabe, N., Shirai, T., Kamiya, H., & Takeuchi, Y. (2005). Morphological differences in cardiovascular anomalies induced by bis-diamine between Sprague-Dawley and Wistar rats. Congenital Anomalies, 45(2), 52–58. https://doi.org/10.1111/j.1741-4520.2005.00063.x Heine, U. I., Roberts, A. B., Munoz, E. F., Roche, N. S., & Sporn, M. B. (1985). Effects of retinoid deficiency on the development of the heart and vascular system of the quail embryo. Virchows Archiv. B, Cell Pathology Including Molecular Pathology, 50(2), 135–152. https://doi.org/10.1007/BF02889897 Kise, K., Nakagawa, M., Okamoto, N., Hanato, T., Watanabe, N., Nishijima, S., Fujino, H., Takeuchi, Y., & Shiraishi, I. (2005). Teratogenic effects of bis-diamine on the developing cardiac conduction system. Birth Defects Research Part A - Clinical and Molecular Teratology, 73(8), 547–554. https://doi.org/10.1002/bdra.20163 Kuribayashi, T., & Roberts, W. C. (1993). Tetralogy of fallot, truncus arteriosus, abnormal myocardial architecture and anomalies of the aortic arch system induced by bis-diamine in rat fetuses. Journal of the American College of Cardiology, 21(3), 768–776. https://doi.org/10.1016/0735-1097(93)90111-D Nishijima, S., Nakagawa, M., Fujino, H., Hanato, T., Okamoto, N., & Shimada, M. (2000). Teratogenic effects of bis-diamine on early embryonic rat heart: An in vitro study. Teratology, 62(2), 115–122. https://doi.org/10.1002/1096-9926(200008)62:2<115::aid-tera8>3.0.co;2-%23 Okamoto, N., Nakagawa, M., Fujino, H., Nishijima, S., Hanato, T., Narita, T., Takeuchi, Y., & Imanaka-Yoshida, K. (2004). Teratogenic Effects of Bis-diamine on the Developing Myocardium. Birth Defects Research Part A - Clinical and Molecular Teratology, 70(3), 132–141. https://doi.org/10.1002/bdra.20001 Okishima, T., Takamura, K., Matsuoka, Y., Ohdo, S., & Hayakawa, K. (1992). Cardiovascular anomalies in chick embryos produced by bis‐diamine in dimethylsulfoxide. Teratology, 45(2), 155–162. https://doi.org/10.1002/tera.1420450209 Tasaka, H., Takenaka, H., Okamoto, N., Onitsuka, T., Koga, Y., & Hamada, M. (1991). Abnormal development of cardiovascular systems in rat embryos treated with bisdiamine. Teratology, 43(3), 191–200. https://doi.org/10.1002/tera.1420430303 Wang, S., Huang, W., Castillo, H. A., Kane, M. A., Xavier-Neto, J., Trainor, P. A., & Moise, A. R. (2018). Alterations in retinoic acid signaling affect the development of the mouse coronary vasculature. Developmental Dynamics, 247(8), 976–991. https://doi.org/10.1002/dvdy.24639 Wilson, J. G., & Warkany, J. (1949). Aortic-arch and cardiac anomalies in the offspring of vitamin A deficient rats. The American Journal of Anatomy, 85(1), 113–155. https://doi.org/10.1002/AJA.1000850106 Wilson, J. G., & Warkany, J. (1950). Cardiac and aortic arch anomalies in the offspring of vitamin A deficient rats correlated with similar human anomalies. Pediatrics, 5(4), 708–725. https://doi.org/10.1542/peds.5.4.708 AOPWiki 2022-02-08T05:30:29

2022-02-15T10:47:59

<upstream-id>5ad763bf-f3cd-43a0-97bf-bb4990596896</upstream-id> <downstream-id>7bba019c-1626-4adc-bf52-1ed3eb1e9272</downstream-id> All-trans retinoic acid (atRA) is the active metabolite of vitamin A in developing mammals and its physiological levels is tightly regulated by enzymatic pathways. This KER is particularly relevant for mammalian embryogenesis/fetal development stages. atRA is synthesized from dietary vitamin A (retinol) by a two-step oxidation pathway (<a href="#_ENREF_3" title="Chatzi, 2013 #14">Chatzi et al, 2013</a>; <a href="#_ENREF_14" title="Kedishvili, 2016 #256">Kedishvili, 2016</a>): 1) retinol dehydrogenase (RDH10) metabolizes retinol to retinaldehyde (reversible step), 2) retinaldehyde dehydrogenase ALDH1A (ALDH1A1, ALDH1A2, ALDH1A3) metabolizes retinaldehyde to RA (irreversible step). All three isoenzymes can carry out the second (irreversible step) to produce atRA, but ALDH1A2 is the most active form during development (<a href="#_ENREF_14" title="Kedishvili, 2016 #256">Kedishvili, 2016</a>). Thus, inhibition of ALDH1A2 during development will decrease atRA concentrations.

This KER is considered canonical knowledge and supporting literature was sourced from e.g. key review articles from open literature. I.e. evidence was not sourced by systematic literature search strategies.

Evidence showing that retinaldehyde dehydrogenases is responsible for the irreversible oxidation of retinal to retinoic acid was provided by several studies in the 1960s, using calf and rat livers (<a href="#_ENREF_5" title="Dmitrovskii, 1961 #257">Dmitrovskii, 1961</a>; <a href="#_ENREF_6" title="Dunagin Jr, 1964 #261">Dunagin Jr et al, 1964</a>; <a href="#_ENREF_8" title="Elder, 1962 #259">Elder & Topper, 1962</a>; <a href="#_ENREF_10" title="Futterman, 1962 #258">Futterman, 1962</a>; <a href="#_ENREF_15" title="Lakshmanan, 1964 #262">Lakshmanan et al, 1964</a>; <a href="#_ENREF_17" title="Mahadevan, 1962 #260">Mahadevan et al, 1962</a>), as reviewed by (<a href="#_ENREF_14" title="Kedishvili, 2016 #256">Kedishvili, 2016</a>). The identification of the three isoenzymes ALDH1A1 (RALDH1), ALDH1A2 (RALDH2), ALDH1A3 (RALDH3) followed during 1980-1990 (<a href="#_ENREF_14" title="Kedishvili, 2016 #256">Kedishvili, 2016</a>). It is now considered canonical knowledge that the three retinaldehyde dehydrogenases are responsible for the in vivo biosynthesis of retinoic acid from retinal (<a href="#_ENREF_18" title="Marchitti, 2008 #264">Marchitti et al, 2008</a>; <a href="#_ENREF_21" title="Napoli, 2012 #263">Napoli, 2012</a>).

Embryogenesis/fetal development in mammals Of the three isoenzymes, ALDH1A2 is the most active form during early development in mammals. This is evidenced in mice ablated for Aldh1a2 (Raldh2-/-), which are incapable of producing atRA and present with severe developmental defects (<a href="#_ENREF_23" title="Niederreither, 1999 #19">Niederreither et al, 1999</a>). Conversely, mice lacking Aldh1a1 or Aldh1a3 survive fetal development, with phenotypes presenting postnatally (<a href="#_ENREF_7" title="Dupé, 2003 #265">Dupé et al, 2003</a>; <a href="#_ENREF_9" title="Fan, 2003 #266">Fan et al, 2003</a>; <a href="#_ENREF_20" title="Molotkov, 2003 #267">Molotkov & Duester, 2003</a>). Thus, the biological plausibility that inhibition of ALDH1A2 will lead to decreased atRA in cells and tissues during development is strong.

The empirical evidence for linkage is strong and widely accepted. The enzymatic activity of ALDH1A2 and capacity to oxidize retinal has been proven in vitro (see KE 1880). In vivo, the strongest evidence comes from the Aldh1a2-deficient mice that fail to synthesize retinoic acid during embryogenesis (<a href="#_ENREF_23" title="Niederreither, 1999 #19">Niederreither et al, 1999</a>). Additionally, ovary culture with the potent ALDH1A2 inhibitor WIN18,446 results in failure to upregulate the atRA-regulated gene Stra8 in oocytes, resulting in germ cell loss (<a href="#_ENREF_27" title="Rosario, 2020 #110">Rosario et al, 2020</a>). Additional evidence for this relationship using WIN18,466 also comes from in vivo studies looking at spermatogenesis; inhibition of ALDH1A2 via WIN18,466 results in loss of atRA expression and halted spermatogenesis in diverse species such as mice, rabbits and zebrafish (<a href="#_ENREF_1" title="Amory, 2011 #270">Amory et al, 2011</a>; <a href="#_ENREF_25" title="Paik, 2014 #269">Paik et al, 2014</a>; <a href="#_ENREF_26" title="Pradhan, 2015 #271">Pradhan & Olsson, 2015</a>).

There are redundant pathways for atRA synthesis (e.g. ALDH isoforms) which may buffer a decrease in atRA concentrations caused by reduced ALDH1A activity, complicating the prediction of changes to atRA concentration. There is also tissue-specific expression of various components of the atRA synthesis pathways, which introduces additional variability in atRA concentration outcomes depending on biological context.

The distribution of retinoic acid in cells and tissues are highly variable, as has been shown across species including chicken (<a href="#_ENREF_16" title="Maden, 1998 #273">Maden et al, 1998</a>), frogs (<a href="#_ENREF_4" title="Chen, 1994 #277">Chen et al, 1994</a>), mice (<a href="#_ENREF_11" title="Kane, 2005 #274">Kane et al, 2005</a>; <a href="#_ENREF_24" title="Obrochta, 2014 #278">Obrochta et al, 2014</a>) and rats (<a href="#_ENREF_2" title="Bhat, 1997 #272">Bhat, 1997</a>), as well as serum/plasma from humans (<a href="#_ENREF_12" title="Kane, 2008 #279">Kane et al, 2008</a>; <a href="#_ENREF_19" title="Miyagi, 2001 #275">Miyagi et al, 2001</a>; <a href="#_ENREF_22" title="Napoli, 1985 #276">Napoli et al, 1985</a>). The exact relationship between ALDH1A2 inhibition and resulting atRA concentrations in mammalian ovaries is unclear. The ALDH1A2 inhibitor WIN18,446 inhibits enzyme activity in vitro with an IC(50) of 0.3 μM (<a href="#_ENREF_1" title="Amory, 2011 #270">Amory et al, 2011</a>), and a dose of only 0.01 µM is sufficient to significantly reduce expression of Stra8 in cultured mouse fetal ovaries and with actual loss of oocytes from 2 µM (<a href="#_ENREF_27" title="Rosario, 2020 #110">Rosario et al, 2020</a>).

Since atRA must be enzymatically synthesized by ALDH1A enzymes (in this case ALDH1A2), the temporal and linear relationship between the two KEs are essential.

Retinoic acid status is regulated by complex feedback loops. For instance, atRA induces expression of retinoid enzymes to promote synthesis of retinyl esters, but simultaneously atRA induces expression of its own catabolizing CYP26 enzymes (<a href="#_ENREF_13" style="color:#0563c1; text-decoration:underline" title="Kedishvili, 2013 #35">Kedishvili, 2013</a>; <a href="#_ENREF_14" style="color:#0563c1; text-decoration:underline" title="Kedishvili, 2016 #256">Kedishvili, 2016</a>; <a href="#_ENREF_28" style="color:#0563c1; text-decoration:underline" title="Teletin, 2017 #48">Teletin et al, 2017</a>).

High Male High Female

Not Specified

All life stages

High High High

<a name="_ENREF_1">Amory JK, Muller CH, Shimshoni JA, Isoherranen N, Paik J, Moreb JS, Amory Sr DW, Evanoff R, Goldstein AS, Griswold MD (2011) Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis. J Androl 32: 111-119</a> <a name="_ENREF_2">Bhat PV (1997) Tissue concentrations of retinol, retinyl esters, and retinoic acid in vitamin A deficient rats administered a single dose of radioactive retinol. Can J Physiol Pharmacol 75: 74-77</a> <a name="_ENREF_3">Chatzi C, Cunningham TJ, Duester G (2013) Investigation of retinoic acid function during embryonic brain development using retinaldehyde-rescued Rdh10 knockout mice. Dev Dyn 242: 1056-1065</a> <a name="_ENREF_4">Chen Y, Huang L, Solursh M (1994) A concentration gradient of retinoids in the early Xenopus laevis embryo. Dev Biol 161: 70-76</a> <a name="_ENREF_5">Dmitrovskii AA (1961) Oxidation of vitamin A aldehyde to vitamin A acid catalyzed by aldehyde oxidase. Biokhimiya 26: 126</a> <a name="_ENREF_6">Dunagin Jr PE, Zachman RD, Olson JA (1964) Identification of free and conjugated retinoic acid as a product of retinal (vitamin A aldehyde) metabolism in the rat in vivo. Biochim Biophys Acta 90: 432-434</a> <a name="_ENREF_7">Dupé V, Matt N, Garnier JM, Chambon P, Mark M, Ghyselinck NB (2003) A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment. Proc Natl Acad Sci U S A 100: 14036-14041</a> <a name="_ENREF_8">Elder TD, Topper YJ (1962) The oxidation of retinene (vitamin A1 aldehyde) to vitamin A acid by mammalian steroid-sensitive aldehyde dehydrogenase. Biochim Biophys Acta 64: 430</a> <a name="_ENREF_9">Fan X, Molotkov A, Manabe SI, Donmoyer CM, Deltour L, Foglio MH, Cuenca AE, Blaner WS, Lipton SA, Duester G (2003) Targeted disruption of Aldh1a1 (Raldh1) provides evidence for a complex mechanism of retinoic acid synthesis in the developing retina. Mol Cell Biol 23: 4637-4648</a> <a name="_ENREF_10">Futterman S (1962) Enzymatic oxidation of vitamin A aldehyde to vitamin A acid. J Biol Chem 237: 677-680</a> <a name="_ENREF_11">Kane MA, Chen N, Sparks S, Napoli JL (2005) Quantification of endogenous retinoic acid in limited biological samples by LC/MS/MS. Biochem J 388: 363-369</a> <a name="_ENREF_12">Kane MA, Folias AE, Napoli JL (2008) HPLC/UV quantitation of retinal, retinol, and retinyl esters in serum and tissues. Anal Biochem 378: 71-79</a> <a name="_ENREF_13">Kedishvili NY (2013) Enzymology of retinoic acid biosynthesis and degradation. J Lipid Res 54: 1744-1760</a> <a name="_ENREF_14">Kedishvili NY (2016) Retinoic Acid Synthesis and Degradation. Subcell Biochem 81: 127-161</a>   <a name="_ENREF_15">Lakshmanan MR, Vaidyanathan CS, Cama HR (1964) Oxidation of vitamin A1 aldehyde and vitamin A2 aldehyde to the corresponding acids by aldehyde oxidase from different species. Biochem J 90: 569-573</a> <a name="_ENREF_16">Maden M, Sonneveld E, van der Saag PT, Gale E (1998) The distribution of endogenous retinoic acid in the chick embryo: implications for developmental mechanisms. Development 125: 4133-4144</a> <a name="_ENREF_17">Mahadevan S, Murthy SK, Ganguly J (1962) Enzymic oxidation of vitamin A aldehyde to vitamin A acid by rat liver. Biochem J 85: 326-331</a> <a name="_ENREF_18">Marchitti SA, Brocker C, Stagos D, Vasiliou V (2008) Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert Opin Drug Metab Toxicol 4: 697-720</a> <a name="_ENREF_19">Miyagi M, Yokoyama H, Shiraishi H, Matsumoto M, Ishii H (2001) Simultaneous quantification of retinol, retinal, and retinoic acid isomers by high-performance liquid chromatography with a simple gradiation. J Chromatogr B Biomed Sci Appl 757: 365-368</a> <a name="_ENREF_20">Molotkov A, Duester G (2003) Genetic evidence that retinaldehyde dehydrogenase Raldh1 (Aldh1a1) functions downstream of alcohol dehydrogenase Adh1 in metabolism of retinol to retinoic acid. J Biol Chem 278: 36085-36090</a> <a name="_ENREF_21">Napoli JL (2012) Physiological insights into all-trans-retinoic acid biosynthesis. Biochim Biophys Acta 1821: 152-167</a> <a name="_ENREF_22">Napoli JL, Pramanik BC, Williams JB, Dawson MI, Hobbs PD (1985) Quantification of retinoic acid by gas-liquid chromatography-mass spectrometry: total versus all-trans-retinoic acid in human plasma. J Lipid Res 26: 387-392</a> <a name="_ENREF_23">Niederreither K, Subbarayan V, Dollé P, Chambon P (1999) Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 21: 444-448</a> <a name="_ENREF_24">Obrochta KM, Kane MA, Napoli JL (2014) Effects of diet and strain on mouse serum and tissue retinoid concentrations. PLoS One 9: e99435</a> <a name="_ENREF_25">Paik J, Haenisch M, Muller CH, Goldstein AS, Arnold S, Isoherranen N, Brabb T, Treuting PM, Amory JK (2014) Inhibition of retinoic acid biosynthesis by the bisdichloroacetyldiamine WIN 18,446 markedly suppresses spermatogenesis and alters retinoid metabolism in mice. J Biol Chem 289: 15104-15117</a> <a name="_ENREF_26">Pradhan A, Olsson PE (2015) Inhibition of retinoic acid synthesis disrupts spermatogenesis and fecundity in zebrafish. Gen Comp Endocrinol 217-218: 81-91</a> <a name="_ENREF_27">Rosario R, Stewart HL, Walshe E, Anderson RA (2020) Reduced retinoic acid synthesis accelerates prophase I and follicle activation. Reproduction 160: 331-341</a> <a name="_ENREF_28">Teletin M, Vernet N, Ghyselinck NB, Mark M (2017) Roles of Retinoic Acid in Germ Cell Differentiation. Curr Top Dev Biol 125: 191-225</a>   AOPWiki 2021-05-24T11:40:55

2024-12-18T03:16:10

<upstream-id>7bba019c-1626-4adc-bf52-1ed3eb1e9272</upstream-id> <downstream-id>233a78cb-fbd8-49e7-ba5e-8357f4ced68a</downstream-id> The biological plausibility between the ATRA gradient stimulating the patterning of the SHF is high, because vertebrate embryo-fetal cardiovascular development involves multiple steps and great knowledge is available including the importance of all-trans retinoic acid (ATRA) which has been reviewed in multiple papers (Brade et al., 2018; Duong & Waxman, 2021; Nakajima, 2019; Perl & Waxman, 2019; Stefanovic & Zaffran, 2017; S. Wang & Moise, 2019). As different processes in embryodevelopment benefit from varying levels of ATRA, an ATRA gradient exists which is generated by multiple enzymes that synthesize and degrade ATRA to maintain the preferred balance (Kedishvili, 2013; Menegola et al., 2021; Tonk & Pennings, 2015). In case cells sense high ATRA levels, proteins involved in ATRA degradation or storage are stimulated (STRA6, DHRS3, CRBP1, CRABP2, LRAT, CYP26A1) and proteins involved in ATRA generation are decreased in expression (RBP4, RDH10, ALDH1A2). In case cells sense low ATRA levels, proteins involved in ATRA generation are stimulated (RBP4, RDH10, ALDH1A2) and proteins involved in ATRA degradation or storage are decreased in expression (STRA6, DHRS3, CRBP1, CRABP2, LRAT, CYP26A1) (Duong & Waxman, 2021). This ATRA gradient during cardiovascular development induces correct patterning of progenitor cells and later correct looping of the heart tube to form a four-chambered heart including formation of the great vessels. In case this gradient is disturbed, cardiovascular developmental defects can occur (Nakajima, 2019; Perl & Waxman, 2019; Sirbu et al., 2020; Stefanovic & Zaffran, 2017).

The evidence for this KER has been studied in chick, zebrafish, and murine studies. The biological plausibility for ATRA involved in second heart field (SHF) patterning and signaling is strong. The human evidence on the other hand is not well known and although evolutionary there are many resemblances across species, there may be differences with human biology. The second heart field is patterned along an anterior and posterior axis, which is important for consequent predispositioning to specific anatomical parts/occurrences in cardiovascular development. After the initial patterning stages, the size of the cardiac progenitor pool is controlled within the anterior lateral plate mesoderm, ATRA signaling then divides the anterior and posterior SHFs (Keegan et al., 2005; S. Wang & Moise, 2019). High ATRA signaling defines the posterior boundary of the murine second heart field (Ryckebusch et al., 2008a; Sirbu et al., 2008). This is exemplified by the ATRA producing enzyme RALDH, which is expressed in posterior SHF progenitors in mice (Stefanovic et al., 2020). When comparing species, data from ATRA-deficient mice implied that ATRA signaling primarily affects SHF progenitor differentiation at the arterial and venous poles (Ryckebusch et al., 2008a; Sirbu et al., 2008), while data examining ATRA-deficient zebrafish suggested these embryos have enlarged hearts with an increase in FHF-derived cardiomyocytes (Duong & Waxman, 2021; Waxman et al., 2008). ATRA signaling promotes expression of Tbx5 within the posterior SHF (de Bono et al., 2018; Duong & Waxman, 2021). Consequently, Tbx5 inhibits Tbx1 in the anterior SHF. Mef2c activation also needs ATRA signaling within the SHF progenitors (P. Li et al., 2010). ATRA signaling represses Fgf8 (Sorrell & Waxman, 2011). ATRA signaling activates Hox genes (Langston & Gudas, 1992; Marshall et al., 1996; Zhang et al., 2000). Hoxa3 expression in the SHF depends on ATRA signaling (Bertrand et al., 2011). Also, Hoxa1 (Ryckebusch et al., 2008a) and Hoxb1 are involved in SHF patterning (Bertrand et al., 2011; Dollé et al., 2010; Hochgreb et al., 2003; P. Li et al., 2010; Moss et al., 1998; Roux et al., 2015; Ryckebusch et al., 2008a; Sirbu et al., 2008; Stefanovic et al., 2020). All these genes are involved in AP patterning.

The evidence for the relationship of ATRA gradient formation and SHF patterning is well established and nicely summarized by Nakajima (2019). The posterior part of the SHF is in need of a strong ATRA signaling that inhibits Tbx1 to define the posterior SHF boundary. Low-weak ATRA signaling stimulates the expression of Tbx1 in the anterior SHF. The anterior SHF consists of progenitors for the formation of the outflow tract (OFT). Additionally, the anterior SHF’s cranial segments consisting of pharyngeal arches 1-2 and are responsible for the formation of the right ventricle and proximal OFT. The anterior SHF’s caudal segments consisting of the pharyngeal arches 3-6 are responsible for distal OFT formation and the ascending aorta (AA). The aortic arch within pharyngeal arch 4 will eventually form the ascending aorta. Evidence for this relationship mainly comes from knockout studies. Mutations of the Rdh and Raldh2 gene result in phenotypes characterized by prominent myocardial defects as severe ventricular myocardium hypoplasia resulting in embryonic lethality (Brade et al., 2011; el Robrini et al., 2016; Merki et al., 2005; Niederreither et al., 1997, 2001; Sorrell & Waxman, 2011; Stefanovic & Zaffran, 2017; S. Wang & Moise, 2019). These Raldh2 mouse mutant embryos show a disruption of the posterior limit of the SHF starting at E7.5 (Duong & Waxman, 2021; Ryckebusch et al., 2008a; Sirbu et al., 2008). Excess exposure in human to vitamin A or the analogues (e.g. ATRA), can cause defects including conotruncal and aortic arch artery malformations like great vessel transposition, right ventricle double outlet, and teratology of Fallot (Stefanovic & Zaffran, 2017). This is also observed when rodents were treated with ATRA including transposition of great arteries and patterning defects (Stefanovic & Zaffran, 2017). In vitro experiments confirmed the in vivo observations because cultured SHF progenitors failed to differentiate from the arterial pole of Aldh1a2KO mice (Ryckebusch et al., 2008b).

ATRA levels can also be diminished through a feedback loop by for instance Cyp26. For creating an ATRA gradient, the Cyp26a1 negative feedback loop is critical as was confirmed when coupling in vivo zebrafish studies with mathematical modeling (A. Q. Cai et al., 2012; Duong & Waxman, 2021; Schilling et al., 2012; White et al., 2007).

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Bertrand, N., Roux, M., Ryckebüsch, L., Niederreither, K., Dollé, P., Moon, A., Capecchi, M., & Zaffran, S. (2011). Hox genes define distinct progenitor sub-domains within the second heart field. Developmental Biology, 353(2), 266–274. https://doi.org/10.1016/J.YDBIO.2011.02.029 Brade, T., Kumar, S., Cunningham, T. J., Chatzi, C., Zhao, X., Cavallero, S., Li, P., Sucov, H. M., Ruiz-Lozano, P., & Duester, G. (2011). Retinoic acid stimulates myocardial expansion by induction of hepatic erythropoietin which activates epicardial Igf2. Development, 138(1), 139–148. https://doi.org/10.1242/dev.054239 Brade, T., Pane, L. S., Moretti, A., Chien, K. R., & Laugwitz, K.-L. (2018). Embryonic Heart Progenitors and Cardiogenesis. 1–18. https://doi.org/10.1101/cshperspect.a013847 Cai, A. Q., Radtke, K., Linville, A., Lander, A. D., Nie, Q., & Schilling, T. F. (2012). Cellular retinoic acid-binding proteins are essential for hindbrain patterning and signal robustness in zebrafish. Development (Cambridge, England), 139(12), 2150–2155. https://doi.org/10.1242/DEV.077065 de Bono, C., Thellier, C., Bertrand, N., Sturny, R., Jullian, E., Cortes, C., Stefanovic, S., Zaffran, S., Théveniau-Ruissy, M., & Kelly, R. G. (2018). T-box genes and retinoic acid signaling regulate the segregation of arterial and venous pole progenitor cells in the murine second heart field. Human Molecular Genetics, 27(21), 3747–3760. https://doi.org/10.1093/HMG/DDY266 Dollé, P., Fraulob, V., Gallego-Llamas, J., Vermot, J., & Niederreither, K. (2010). Fate of retinoic acid-activated embryonic cell lineages. Developmental Dynamics : An Official Publication of the American Association of Anatomists, 239(12), 3260–3274. https://doi.org/10.1002/DVDY.22479 Duong, T. B., & Waxman, J. S. (2021). Patterning of vertebrate cardiac progenitor fields by retinoic acid signaling. Genesis (New York, N.Y. : 2000), e23458. https://doi.org/10.1002/dvg.23458 el Robrini, N., Etchevers, H. C., Ryckebüsch, L., Faure, E., Eudes, N., Niederreither, K., Zaffran, S., & Bertrand, N. (2016). Cardiac outflow morphogenesis depends on effects of retinoic acid signaling on multiple cell lineages. Developmental Dynamics, 245(3), 388–401. https://doi.org/10.1002/dvdy.24357 Hochgreb, T., Linhares, V. L., Menezes, D. C., Sampaio, A. C., Yan, C. Y. I., Cardoso, W. v., Rosenthal, N., & Xavier-Neto, J. (2003). A caudorostral wave of RALDH2 conveys anteroposterior information to the cardiac field. Development, 130(22), 5363–5374. https://doi.org/10.1242/DEV.00750 Kedishvili, N. Y. (2013). Enzymology of retinoic acid biosynthesis and degradation. Journal of Lipid Research, 54(7), 1744–1760. https://doi.org/10.1194/JLR.R037028 Keegan, B. R., Feldman, J. L., Begemann, G., Ingham, P. W., & Yelon, D. (2005). Retinoic acid signaling restricts the cardiac progenitor pool. Science (New York, N.Y.), 307(5707), 247–249. https://doi.org/10.1126/SCIENCE.1101573 Langston, A. W., & Gudas, L. J. (1992). Identification of a retinoic acid responsive enhancer 3’ of the murine homeobox gene Hox-1.6. Mechanisms of Development, 38(3), 217–227. https://doi.org/10.1016/0925-4773(92)90055-O Li, P., Pashmforoush, M., & Sucov, H. M. (2010). Retinoic Acid Regulates Differentiation of the Secondary Heart Field and TGFβ-Mediated Outflow Tract Septation. Developmental Cell, 18(3), 480–485. https://doi.org/10.1016/J.DEVCEL.2009.12.019/ATTACHMENT/B413E05D-04E2-4F76-9417-72BF1FD02515/MMC1.PDF Marshall, H., Morrison, A., Studer, M., Popperl, H., & Krumlauf’, R. (1996). Retinoids and Hox genes. The FASEB Journal, 10(9), 969–978. https://doi.org/10.1096/FASEBJ.10.9.8801179 Menegola, E., Veltman, C. H. J., Battistoni, M., di Renzo, F., Moretto, A., Metruccio, F., Beronius, A., Zilliacus, J., Kyriakopoulou, K., Spyropoulou, A., Machera, K., van der Ven, L. T. M., & Luijten, M. (2021). An adverse outcome pathway on the disruption of retinoic acid metabolism leading to developmental craniofacial defects. Toxicology, 458. https://doi.org/10.1016/J.TOX.2021.152843 Merki, E., Zamora, M., Raya, A., Kawakami, Y., Wang, J., Zhang, X., Burch, J., Kubalak, S. W., Kaliman, P., Belmonte, J. C. I., Chien, K. R., & Ruiz-Lozano, P. (2005). Epicardial retinoid X receptor alpha is required for myocardial growth and coronary artery formation. Proceedings of the National Academy of Sciences of the United States of America, 102(51), 18455–18460. https://doi.org/10.1073/PNAS.0504343102 Moss, J. B., Xavier-Neto, J., Shapiro, M. D., Nayeem, S. M., McCaffery, P., Dräger, U. C., & Rosenthal, N. (1998). Dynamic patterns of retinoic acid synthesis and response in the developing mammalian heart. Developmental Biology, 199(1), 55–71. https://doi.org/10.1006/dbio.1998.8911 Nakajima, Y. (2019). Retinoic acid signaling in heart development. Genesis, 57(7). https://doi.org/10.1002/dvg.23300 Niederreither, K., McCaffery, P., Dräger, U. C., Chambon, P., & Dollé, P. (1997). Restricted expression and retinoic acid-induced downregulation of the retinaldehyde dehydrogenase type 2 (RALDH-2) gene during mouse development. Mechanisms of Development, 62(1), 67–78. https://doi.org/10.1016/S0925-4773(96)00653-3 Niederreither, K., Vermot, J., Messaddeq, N., Schuhbaur, B., Chambon, P., & Dollé, P. (2001). Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse. Development (Cambridge, England), 128(7), 1019–1031. https://doi.org/10.1242/dev.128.7.1019 Perl, E., & Waxman, J. S. (2019). Reiterative Mechanisms of Retinoic Acid Signaling during Vertebrate Heart Development. Journal of Developmental Biology, 7(2). https://doi.org/10.3390/jdb7020011 Roux, M., Laforest, B., Capecchi, M., Bertrand, N., & Zaffran, S. (2015). Hoxb1 regulates proliferation and differentiation of second heart field progenitors in pharyngeal mesoderm and genetically interacts with Hoxa1 during cardiac outflow tract development. Developmental Biology, 406(2), 247–258. https://doi.org/10.1016/J.YDBIO.2015.08.015 Ryckebusch, L., Wang, Z., Bertrand, N., Lin, S. C., Chi, X., Schwartz, R., Zaffran, S., & Niederreither, K. (2008a). Retinoic acid deficiency alters second heart field formation. Proceedings of the National Academy of Sciences of the United States of America, 105(8), 2913–2918. https://doi.org/10.1073/PNAS.0712344105 Ryckebusch, L., Wang, Z., Bertrand, N., Lin, S. C., Chi, X., Schwartz, R., Zaffran, S., & Niederreither, K. (2008b). Retinoic acid deficiency alters second heart field formation. Proceedings of the National Academy of Sciences of the United States of America, 105(8), 2913–2918. https://doi.org/10.1073/PNAS.0712344105 Schilling, T. F., Nie, Q., & Lander, A. D. (2012). Dynamics and precision in retinoic acid morphogen gradients. Current Opinion in Genetics & Development, 22(6), 562–569. https://doi.org/10.1016/J.GDE.2012.11.012 Sirbu, I. O., Chiş, A. R., & Moise, A. R. (2020). Role of carotenoids and retinoids during heart development. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, 1865(11). https://doi.org/10.1016/j.bbalip.2020.158636 Sirbu, I. O., Zhao, X., & Duester, G. (2008). Retinoic acid controls heart anteroposterior patterning by down-regulating Isl1 through the Fgf8 pathway. Developmental Dynamics : An Official Publication of the American Association of Anatomists, 237(6), 1627–1635. https://doi.org/10.1002/DVDY.21570 Sorrell, M. R. J., & Waxman, J. S. (2011). Restraint of Fgf8 signaling by retinoic acid signaling is required for proper heart and forelimb formation. Developmental Biology, 358(1), 44–55. https://doi.org/10.1016/J.YDBIO.2011.07.022 Stefanovic, S., Laforest, B., Desvignes, J. P., Lescroart, F., Argiro, L., Maurel-Zaffran, C., Salgado, D., Plaindoux, E., de Bono, C., Pazur, K., Théveniau-Ruissy, M., Béroud, C., Puceat, M., Gavalas, A., Kelly, R. G., & Zaffran, S. (2020). Hox-dependent coordination of mouse cardiac progenitor cell patterning and differentiation. ELife, 9, 1–32. https://doi.org/10.7554/ELIFE.55124 Stefanovic, S., & Zaffran, S. (2017). Mechanisms of retinoic acid signaling during cardiogenesis. Mechanisms of Development, 143, 9–19. https://doi.org/10.1016/j.mod.2016.12.002 Tonk, E. C. M., & Pennings, J. L. A. (2015). An adverse outcome pathway framework for neural tube and axial defects mediated by modulation of retinoic acid homeostasis. Reproductive Toxicology, 55, 104–113. https://doi.org/10.1016/J.REPROTOX.2014.10.008 Wang, S., & Moise, A. R. (2019). Recent insights on the role and regulation of retinoic acid signaling during epicardial development. Genesis, 57(7). https://doi.org/10.1002/dvg.23303 Waxman, J. S., Keegan, B. R., Roberts, R. W., Poss, K. D., & Yelon, D. (2008). Hoxb5b acts downstream of retinoic acid signaling in the forelimb field to restrict heart field potential in zebrafish. Developmental Cell, 15(6), 923–934. https://doi.org/10.1016/J.DEVCEL.2008.09.009 White, R. J., Nie, Q., Lander, A. D., & Schilling, T. F. (2007). Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biology, 5(11), 2522–2533. https://doi.org/10.1371/JOURNAL.PBIO.0050304 Zhang, F., Nagy Kovács, E., & Featherstone, M. S. (2000). Murine hoxd4 expression in the CNS requires multiple elements including a retinoic acid response element. Mechanisms of Development, 96(1), 79–89. https://doi.org/10.1016/S0925-4773(00)00377-4   AOPWiki 2022-02-08T07:11:35

2022-02-15T10:51:14

<upstream-id>233a78cb-fbd8-49e7-ba5e-8357f4ced68a</upstream-id> <downstream-id>90806c92-db8f-4eb8-9c62-450413ec4a87</downstream-id> Interactions between the second heart field (SHF), pharyngeal endoderm and neural crest are needed for heart development and are interdependent. For this reason, the biological plausibility of this connection is moderate as in this KER the effects of impaired SHF patterning on cardiac neural crest cells (cNCC) functioning is addressed (Diman et al., 2011).

Migration of cNCCs from the neural tube through the pharyngeal arches to the cardiac progenitors is required for normal cardiovascular development. Additionally, the cNCCs need to be functional upon arrival. To stimulate this process, signaling molecules are necessary to attract and stimulate the cNCC for contributing to cardiovascular development. Keyte et al. reviewed the evolutionary relevance of cNCCs related to cardiovascular development and conclude that to all vertebrates a common SHF is evolved and the function of cNCCs could have very early roots in vertebrate evolution  (A. L. Keyte et al., 2014). The importance of the SHF in relation to cardiovascular development is shown by ablation studies of SHF specific genes Isl1 and Mef2c which resulted in failed a proper development of heart tube elongation, looping, the right ventricle, the atria, and the OFT (C. L. Cai et al., 2003; Neeb et al., 2013). It is unclear how different SHF subpopulations are involved in respect to cNCC migration and functioning, ablation of specific genes in the SHF/splanchnic mesoderm show defects in cNCC migration and/or functioning. For example, Tbx1 acts mainly in the anterior SHF during normal cardiovascular development and is involved in pharyngeal arch development, which involve formation of the outflow tract (OFT), right ventricle and the aortic arch (Nakajima, 2019). Tbx1 expression is highly conserved in pharyngeal arches of vertebrates (A. L. Keyte et al., 2014). Semaphorin 3C (Sem3C) is also expressed in a subdomain of the SHF, indicates for pulmonary trunk myocardium, and is necessary for NC migration to the hearts’ arterial pole (Vincent & Buckingham, 2010). The cNCC expresses Sem3C receptors PlexinD1 and PlexinA2, which are required for correct OFT development (Vincent & Buckingham, 2010). The protein FGF8 is expressed at high levels in the pharyngeal ectoderm and endoderm adjacent to the cNCC migratory pathway, and at lower levels in the splanchnic mesoderm (SHF) and is a chemoattractant for cNCCs (Hutson et al. 2006; Sato et al. 2011).

The evidence for the relationship between SHF and cNCC is mainly studied by KO/ablation/hypomorphic/mutant studies, mainly in chick and mice and therefore the empirical evidence is low. Human with DiGeorge Syndrome show a plethora of phenotypes including cardiovascular malformations. Mouse models for DiGeorge syndrome indicate a crucial role for Tbx1 (Jerome & Papaioannou, 2001; Lindsay et al., 2001; Merscher et al., 2001; Ryckebusch et al., 2010; Vermot et al., 2003; Yutzey, 2010). Tbx1 is expressed in the pharyngeal ectoderm, endoderm and the SHF in mice, but not in cNCCs (A. L. Keyte et al., 2014; Vitelli et al., 2002). Tbx1 loss specific to the pharyngeal mesoderm (SHF) can negatively impact cNCCs (Diman et al., 2011; Xu et al., 2004). This can result in migration of fewer cNCCs and defects in aorticopulmonary septation. When Tbx1 is mutated in mice, all-trans retinoic acid (ATRA) levels are upregulated (A. L. Keyte et al., 2014). ATRA is not only important in SHF patterning but also in cNCC morphogenesis and therefore a reduction in Tbx1 may affect the signaling between SHF and cNCCs, although other apparent interlineage signaling factors are observed as well (Neeb et al., 2013). Fgf8 expression is also reduced when Tbx1 is mutated in mice (Vitelli et al., 2002). FGF8 hypomorphic and conditional mouse mutants, result in abnormal cNCC apoptosis and therefore possibly a reduced signaling to the cNCCs (Abu-Issa et al., 2002; A. L. Keyte et al., 2014). Overexpression of FGF8 results in a faster migration of a greater cNCCs number. So FGF8 affects cNCCs survival, timing and targeting (A. L. Keyte et al., 2014). Hypomorphs in Fgf8 show the cardiovascular developmental defects in the patterning of the aortic arch (AA), outflow tract (OFT) patterning, double outlet right ventricle (DORV), and persistent truncus arteriosus (PTA) in mice (Jain et al., 2010). Specific SHF Fgf8 mutants result in PTA, OFT, and DORV abnormalities and Nkx2.5-Cre specific Fgf8 deletion (in the broader cardiac expression domain) also included truncated heart tubes (Jain et al., 2010). The evidence of Fgf8 expression being involved in cNCC stimulation and consequently cardiovascular development, seems to be of indirect nature. The direct effectors of Fgf8, the receptors Fgfr1 and Fgfr2 or the adaptor protein FRS2α, showed slightly different defects as compared to Fgf8 mutations and only ablations of these receptors in the SHF but not the endothelium or cNCCs, resulted in reduced SHF proliferation (Jain et al., 2010; Rochais et al., 2009). Therefore, likely an indirect signal to the NCCs is involved, such as through Bmp4, Sema3c, or Wnt signaling (Jain et al., 2010; Rochais et al., 2009). In SHF specific Fgf8 mutants the BMP/TGFβ is affected that consequently perturbs cNCCs migration and development through Smad signaling (A. Keyte & Hutson, 2012; Nie et al., 2008; Park et al., 2008; Vincent & Buckingham, 2010). Nkx2-5-Cre specific Bmp4 deletion may also indicate the signaling factor from the SHF to cNCCs, as this resulted in perturbed OFT formation, interrupted AA, abnormal AA remodeling, and hypoplastic conotruncal cushions (Neeb et al., 2013). When deleting the Bmp receptors Alk2 and Alk3, this resulted in strikingly similar phenotypes as compared to FGF mutants (Jain et al., 2010). This phenomenon was also observed when Smad4 was conditionally deleted (Jain et al., 2010). Fgf8 also affects Sema3C in cNCC. Sema3C is important in targeting migration of cNCCs which contain the Sema3C receptors PlexinA2, PlexinD1, and Neuropilin1 (Nrp1). Both PlexinA2 and Nrp1 knock-out mice show interrupted aortic arch (IAA) and persistent truncus arteriosus (PTA) associated with decreased cNCCs (Chin et al., 2012). Sema3C knock-out mice also show IAA and PTA (A. L. Keyte et al., 2014). Sema3c is stimulated through various factors. In hypomorph Tbx1 mice, Sema3c expression was inhibited in response to reduced Fgf8 expression. When blocking Fgf8 in chicken, this resulted in an ectopic expression of Sema3c and defects in cNCC migration (Kodo et al., 2017). Tbx1 thus regulates Sema3C, which is specifically required by cNCCs (A. L. Keyte et al., 2014). Foxc1/c2 also activates the transcription of Sema3c in the OFT. Gata6 mutation disturbs target genes expression levels including SEMA3C and PlexinA2 (Kodo et al., 2021). An indirect effect of Fgf8 through Wnt could be possible as well (Jain et al., 2010; Rochais et al., 2009). Wnt5a is expressed in the SHF and Wnt5a mutants show DORV and abnormal invasion of NCCs (Rochais et al., 2009). However, these embryos didn’t show alterations in Fgf8, Fgf10 and Tbx1 gene expression levels. This suggests a signaling route from the SHF to cNCCs through noncanonical Wnt signaling. This was supported by the Fz2 receptor, which was transiently expressed in cardiac neural crest cells (Rochais et al., 2009). Notch mediates Fgf8 signaling in the SHF (Jain et al., 2010). Notch interference correlates with a decreased Fgf8 and BMP signaling (High et al., 2009; Park et al., 2008). This is therefore indicative of an indirect effect (Vincent & Buckingham, 2010). In vivo effects of Notch interference in both the SHF or the NCCs resulted in abnormal arterial pole and arch artery phenotypes (High et al., 2007, 2008, 2009; High & Epstein, 2008; Vincent & Buckingham, 2010). The abnormal phenotypes of the OFT including PTA, DORV and AA patterning next to faulty cNCC migration were also observed in SHF deletion of Notch or Jagged1 (High et al., 2009; Jain et al., 2010; A. L. Keyte et al., 2014).

The migration and development of cNCCs not solely depends on SHF signaling. The pharyngeal endoderm also plays an important role in the maintenance and deployment of cNCCs through signaling of sonic hedgehog (Shh) (Goddeeris et al., 2007; Vincent & Buckingham, 2010). In the absence of Shh, the development of proper pharyngeal arches and OFT is affected (Vincent & Buckingham, 2010). Additionally, a possible feedback loop exists between SHF signaling to cNCCs, since ablation of cNCCs results in SHF overproliferation because of excessive Fgf8 signaling (Rochais et al., 2009). Furthermore, NCC deletion of Smad4 leads to abnormal SHF patterning and a shorter OFT. Lastly, Tbx3 loss in NCCs and pharyngeal endoderm also resulted in SHF overproliferation and a shorter OFT (Rochais et al., 2009).

Abu-Issa, R., Smyth, G., Smoak, I., Yamamura, K. I., & Meyers, E. N. (2002). Fgf8 is required for pharyngeal arch and cardiovascular development in the mouse. Development, 129(19), 4613–4625. https://doi.org/10.1242/dev.129.19.4613 Cai, C. L., Liang, X., Shi, Y., Chu, P. H., Pfaff, S. L., Chen, J., & Evans, S. (2003). Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Developmental Cell, 5(6), 877–889. https://doi.org/10.1016/S1534-5807(03)00363-0 Chin, A. J., Saint-Jeannet, J. P., & Lo, C. W. (2012). How insights from cardiovascular developmental biology have impacted the care of infants and children with congenital heart disease. Mechanisms of Development, 129(5–8), 75–97. https://doi.org/10.1016/J.MOD.2012.05.005 Diman, N. Y. S. G., Remacle, S., Bertrand, N., Picard, J. J., Zaffran, S., & Rezsohazy, R. (2011). A retinoic acid responsive Hoxa3 transgene expressed in embryonic pharyngeal endoderm, cardiac neural crest and a subdomain of the second heart field. PloS One, 6(11). https://doi.org/10.1371/JOURNAL.PONE.0027624 Goddeeris, M. M., Schwartz, R., Klingensmith, J., & Meyers, E. N. (2007). Independent requirements for Hedgehog signaling by both the anterior heart field and neural crest cells for outflow tract development. Development (Cambridge, England), 134(8), 1593–1604. https://doi.org/10.1242/DEV.02824 High, F. A., & Epstein, J. A. (2008). The multifaceted role of Notch in cardiac development and disease. Nature Reviews. Genetics, 9(1), 49–61. https://doi.org/10.1038/NRG2279 High, F. A., Jain, R., Stoller, J. Z., Antonucci, N. B., Min, M. L., Loomes, K. M., Kaestner, K. H., Pear, W. S., & Epstein, J. A. (2009). Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development. Journal of Clinical Investigation, 119(7), 1986–1996. https://doi.org/10.1172/JCI38922 High, F. A., Min, M. L., Pear, W. S., Loomes, K. M., Kaestner, K. H., & Epstein, J. A. (2008). Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proceedings of the National Academy of Sciences of the United States of America, 105(6), 1955–1959. https://doi.org/10.1073/PNAS.0709663105 High, F. A., Zhang, M., Proweller, A., Tu, L. L., Parmacek, M. S., Pear, W. S., & Epstein, J. A. (2007). An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. The Journal of Clinical Investigation, 117(2), 353–363. https://doi.org/10.1172/JCI30070 Jain, R., Rentschler, S., & Epstein, J. A. (2010). Notch and cardiac outflow tract development. Annals of the New York Academy of Sciences, 1188, 184–190. https://doi.org/10.1111/j.1749-6632.2009.05099.x Jerome, L. A., & Papaioannou, V. E. (2001). DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nature Genetics, 27(3), 286–291. https://doi.org/10.1038/85845 Keyte, A., & Hutson, M. R. (2012). The neural crest in cardiac congenital anomalies. Differentiation, 84(1), 25–40. https://doi.org/10.1016/j.diff.2012.04.005 Keyte, A. L., Alonzo-Johnsen, M., & Hutson, M. R. (2014). Evolutionary and developmental origins of the cardiac neural crest: Building a divided outflow tract. Birth Defects Research Part C - Embryo Today: Reviews, 102(3), 309–323. https://doi.org/10.1002/BDRC.21076 Kodo, K., Shibata, S., Miyagawa-Tomita, S., Ong, S. G., Takahashi, H., Kume, T., Okano, H., Matsuoka, R., & Yamagishi, H. (2017). Regulation of Sema3c and the Interaction between Cardiac Neural Crest and Second Heart Field during Outflow Tract Development. Scientific Reports, 7(1). https://doi.org/10.1038/S41598-017-06964-9 Kodo, K., Uchida, K., & Yamagishi, H. (2021). Genetic and Cellular Interaction During Cardiovascular Development Implicated in Congenital Heart Diseases. Frontiers in Cardiovascular Medicine, 8. https://doi.org/10.3389/FCVM.2021.653244 Lindsay, E. A., Vitelli, F., Su, H., Morishima, M., Huynh, T., Pramparo, T., Jurecic, V., Ogunrinu, G., Sutherland, H. F., Scambler, P. J., Bradley, A., & Baldini, A. (2001). Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice. Nature, 410(6824), 97–101. https://doi.org/10.1038/35065105 Merscher, S., Funke, B., Epstein, J. A., Heyer, J., Puech, A., Lu, M. M., Xavier, R. J., Demay, M. B., Russell, R. G., Factor, S., Tokooya, K., Jore, B. S., Lopez, M., Pandita, R. K., Lia, M., Carrion, D., Xu, H., Schorle, H., Kobler, J. B., … Kucherlapati, R. (2001). TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome. Cell, 104(4), 619–629. https://doi.org/10.1016/S0092-8674(01)00247-1 Nakajima, Y. (2019). 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Signaling pathways controlling second heart field development. Circulation Research, 104(8), 933–942. https://doi.org/10.1161/CIRCRESAHA.109.194464 Ryckebusch, L., Bertrand, N., Mesbah, K., Bajolle, F., Niederreither, K., Kelly, R. G., & Zaffran, S. (2010). Decreased levels of embryonic retinoic acid synthesis accelerate recovery from arterial growth delay in a mouse model of DiGeorge syndrome. Circulation Research, 106(4), 686–694. https://doi.org/10.1161/CIRCRESAHA.109.205732 Vermot, J., Niederreither, K., Garnier, J. M., Chambon, P., & Dollé, P. (2003). Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice. Proceedings of the National Academy of Sciences of the United States of America, 100(4), 1763–1768. https://doi.org/10.1073/pnas.0437920100 Vincent, S. D., & Buckingham, M. E. (2010). How to make a heart. The origin and regulation of cardiac progenitor cells. Current Topics in Developmental Biology, 90(C), 1–41. https://doi.org/10.1016/S0070-2153(10)90001-X Vitelli, F., Morishima, M., Taddei, I., Lindsay, E. A., & Baldini, A. (2002). Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways. Human Molecular Genetics, 11(8), 915–922. https://doi.org/10.1093/HMG/11.8.915 Xu, H., Morishima, M., Wylie, J. N., Schwartz, R. J., Bruneau, B. G., Lindsay, E. A., & Baldini, A. (2004). Tbx1 has a dual role in the morphogenesis of the cardiac outflow tract. Development (Cambridge, England), 131(13), 3217–3227. https://doi.org/10.1242/DEV.01174 Yutzey, K. E. (2010). Digeorge syndrome, Tbx1, and retinoic acid signaling come full circle. Circulation Research, 106(4), 630–632. https://doi.org/10.1161/CIRCRESAHA.109.215319 AOPWiki 2022-02-08T07:12:05

2022-02-10T03:33:24

<upstream-id>90806c92-db8f-4eb8-9c62-450413ec4a87</upstream-id> <downstream-id>36e3a1da-0684-4a80-aba5-365d0805a49f</downstream-id> Neural crest cells (NCCs) migrate into the pharyngeal arches 3, 4, and 6. The cardiac NCCs (cNCCs) differentiate into smooth muscle cells (SMCs) between E10.5-E13.5 in mice and between HH14-HH28 in chicken. The left fourth pharyngeal arch artery (PAA) in mammals persists and forms the segment of the aortic arch (AA) connecting the aortic sac and the descending aorta. The sixth PAA will form the pulmonary veins.

The biological plausibility of this relationship is high. Abnormal cNCCs in mouse mutants show regression of the left fourth PAA resulting in an interrupted aortic arch (IAA) also referred to as type b interruption. cNCCs contribute to outflow tract (OFT) septation, vascular remodeling, cardiac valve formation, and possibly also to myocardial development and the conduction system (Plein et al., 2015). When comparing PAA development between taxa there is a difference in aortic arch anatomy. Avian species have a right-sided aortic arch and mammals have a left-sided aortic arch (Gittenberger-de Groot et al., 2006). The relationship between cNCCs and transposition of the great arteries became for the first time very clear in the chick-ablation model by Kirby et al. that showed a spectrum of aortic arch malformations with the fourth and sixth segments as being most vulnerable (Hutson & Kirby, 2007; Kirby, 1993; Kirby et al., 1983; Kirby & Waldo, 1995). This model was more difficult to copy in mammals, yet mouse knock-out models of endothelin 1, semaphoring 3 and Vegf164 could be traced to disturbed NCC migration and differentiation (Gittenberger-de Groot et al., 2006). As the role of cNCCs in OFT septation and aortic arch remodeling is critical in birds and mammals, this is less well understood in vertebrates (Chin et al., 2012). Zebrafish have a different circulation system as compared to mammals and e.g. don’t have a separate systemic and pulmonary circulation or an OFT septum, but they do have cNCCs. The cNCCs in zebrafish arise from a broader region of the neural tube and contributes to all cardiac regions (Chin et al., 2012; Sato et al., 2006).

Evidence for the relationship between cNCCs and transposition of the great arteries mainly resides from cNCCs ablation studies and later also from gene expression knock-out studies. Evidence for quantitative relationships is low. From the chick-ablation study specific to cNCCs, the third, fourth and sixth PAAs were targeted and showed the formation of PAAs being transformed and remodeled into the asymmetric great arteries (Kirby et al., 1983). The cNCCs differentiate into SMCs of the AA arteries for their patterning and persistence. However, they are not necessarily required for formation of these arteries (Porras & Brown, 2008). cNCC ablation in the chick model led to a malformed OFT and AA like persistent truncus arteriosus (PTA), teratology of Fallot and interrupted AA type B, overriding aorta, and ventricular septal defects (Creazzo et al., 1998; Kirby, 1993; Porras & Brown, 2008). Studying the cNCC contribution to cardiovascular development in mammals was more difficult because of a lack of appropriate cNCC markers and it was difficult to manipulate embryonic tissue in mice (Creazzo et al., 1998). The cNCC in mammals was first mapped using a transgenic Lac-Z line (Aoto et al., 2015). Afterwards, cNCCs were studied using a Cre-Lox to lineage in Wnt1-Cre and Pax3-Cre mice (Jiang et al., 2000; Waldo et al., 1996). The heart defects that were observed in the chick ablation model as reviewed by Creazzo et al., were also found in mammals when Pax3 was knocked-out in mouse NCCs, which also resulted in alterations of connexin 43 expression in the ascending aorta (Creazzo et al., 1998; Jain et al., 2011). Looking at AA anomalies, multiple genes related to cNCCs can be disturbed and were reviewed by Kemeda in 2009 (Kameda, 2009). Such genes involved Pax3, Alk5 (receptor of Tgfβ), Alk2 (Bmp type 1 receptor), and semaphoring 3C (Kameda, 2009). VEGF also has a role in OFT and PAA remodeling (Stalmans et al 2003). Furthermore, signaling pathways in mice such as the endothelin pathway (Clouthier et al., 1998; Kurihara et al., 1995; Morishima et al., 2003), but also mutation in TGFβ, BMP, and Smad resulted in impaired AA patterning resulted in impaired AA patterning (Molin et al., 2004; Nie et al., 2008). TGFβ2 mouse KOs also showed OFT and AA defects, and is particularly important to vascular remodeling (Kubalak et al., 2002). Various KO genes specific to cNCCs resulted in IAA where some genes showed to affect migration and others affected subsequent development. cNCC loss of the TGFβ receptor II (Tgfbr2) showed disturbed SMC differentiation and remodeling of the OFT and PAAs in mice (Wurdak et al., 2005). However, in another NCC specific Tgfbr2 mutant study, no altered NCC specification to SMC developed, but cardiovascular malformation PTA and IAA-B did develop (Choudhary et al., 2006). Specific NCC loss of the ALK5 (TGFβ receptor) also caused PAA and OFT defects because of impaired postmigratory cNCC survival (J. Wang et al., 2006). NCC targeted deletion of Fak (focal adhesion kinase), involved in integrin, FGF, and TGFβ pathways, led to PTA, overriding aorta, ventricular septal defect, and type B interruption of the aortic arch (Vallejo-Illarramendi et al., 2009). Downstream effectors of Fak include Cdc42, Crkl, and Erk1/2 involved in cytoskeletal reorganization (Vallejo-Illarramendi et al., 2009). Cell division cycle 42 (cdc42) regulates cytoskeleton remodeling as a molecular switch and its deletion in mouse NCCs caused a halted NCC migration midway the pharyngeal arches that eventually resulted in PTA, hypomorphic pulmonary arteries, IAA and right sided aortic arches (Liu et al., 2013). The Sem3c pathway also seems to be involved in the relationship between cNCCs and great artery formation. NCCs GATA6 inactivation results in PTA and IAA and similar inactivation in SMCs showed the same defects. These observed defects were associated with dysregulated Sem3c expression (Lepore et al., 2006). NRP1 (SEMA3C receptor) KO in cNCCs altered migration in chicken (Toyofuku et al., 2008). Mice lacking NRP1 and NRP2 also show AA and OFT defects (Gu et al., 2003). However, proof for SEMA3C to be involved in mammalian cNCCs is lacking (Plein et al., 2015). In fact, the exact role of cNCCs in the asymmetry of vascular remodeling is not completely understood (Plein et al., 2015). Mice with NCC specific Notch inactivation resulted in AA patterning defects, pulmonary artery stenosis, and ventricular septal defects and plays both in vitro and in vivo a role in cNCC differentiation to SMCs (High et al., 2007; Jain et al., 2010). A mutation of the gene MAML, which is under the Pax3 promotor, can block Notch signaling (Manderfield et al., 2012; Yamagishi, 2021).

Despite the seemingly clear role of cNCCs in great artery formation, also other progenitors contribute to AAA remodeling that are in cross-talk with the cNCCs, such as the pharyngeal mesoderm and endoderm (Franco & Campione, 2003; Gittenberger-de Groot et al., 2006). Furthermore, cNCC ablation also results in altered SHF proliferation and abnormal myocardial function as secondary effects (Farrell et al., 2001; Farrell & Kirby, 2001; Leatherbury et al., 1990; Waldo et al., 2005).

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2022-02-15T10:53:27

Inhibition of RALDH2 causes reduced all-trans retinoic acid levels, leading to transposition of the great arteries

RALDH2 and cardiovascular developmental defects

Gina Mennen

R.H. Mennen, S. Mitchell-Ryan Health and Environmental Sciences Institute (HESI), Washington DC, USA

BY-SA

2.0

The aim was to describe a linear AOP of the relationship between inhibition of retinaldehyde dehydrogenase (RALDH), an all-trans retinoic acid (ATRA) synthesizing enzyme, and the subsequent disturbance of ATRA levels that can influence<s> </s>impaired positioning of the great arteries as the adverse outcome (AO) during cardiovascular development. The selected molecular initiating event (MIE) is inhibition of RALDH. This MIE was selected based on robust available literature. Intermediate key events (KE) are decreased ATRA concentration, disruption of progenitor cells of the second heart field (SHF), and reduced neural crest cell (NCC) migration. Evidence for this AOP is mainly generated in chick and mouse ablation or gene mutation studies. Human evidence is limited, but comparable mechanisms between vertebrates have been reported, thereby establishing relevance due to similarities in cardiovascular development. Impaired great artery positioning is related to reduced cardiovascular function that can result in fetal/embryonic preterm deaths or require surgical intervention to correct defects in newborns. Various factors can influence the formation of the cardiovascular system and the interplay between the pharyngeal endoderm, the splanchnic mesoderm (second heart field) and the neural crest is of importance for proper development. This AOP describes the influence of the secondary heart field (SHF) on cardiac neural crest cell migration and functioning, which in turn is essential for development of the great arteries.   Vertebrate embryo-fetal cardiovascular development involves multiple steps. The importance of all-trans retinoic acid (ATRA) in this process is well documented and has been the subject of multiple review papers (Brade et al., 2018; Duong & Waxman, 2021; Nakajima, 2019; Perl & Waxman, 2019; Stefanovic & Zaffran, 2017; S. Wang & Moise, 2019). <h4>Cardiac progenitors</h4> During early gastrulation at E6.5 in mice, the first cardiac progenitors are formed around the primitive streak and migrate anterior laterally to form the cardiac crescent to become the first heart field (FHF) at E7-7.5 (Stefanovic & Zaffran, 2017). An evolutionary approach to cardiac development related to the vertebrate heart was reviewed by Pérez-Pomares et al. in 2009 (Pérez-Pomares et al., 2009). To make the cardiac crescent and primary heart tube, weak or no ATRA signaling is sufficient (Nakajima, 2019). At this stage of cardiogenesis, ATRA controls the cardiac progenitor pool size (Keegan et al., 2005; S. Wang & Moise, 2019). This early requirement of ATRA is conserved across species and restricts ventricular and atrial specification within the cardiac progenitor pool (Duong & Waxman, 2021). Before the primitive heart tube is formed, ATRA signaling is symmetrical (Nakajima, 2019). <h4>Tube formation and anterior/posterior heart segments before looping</h4> The heart tube is derived from the FHF at E8 in mice or after three weeks in human development (Brade et al., 2018). As the cardiac crescent folds, it will form the primitive heart tube and consequently fusion and systemic circulation can emerge (S. Wang & Moise, 2019). The FHF mainly will give rise to the left ventricle. The linear heart tube expands by cell proliferation and recruitment of additional cells that contribute to the arterial and venous poles of the heart tube and are derived from the second heart field (SHF) (Brade et al., 2018). The SHF mainly contributes to the outflow tract (OFT), the right ventricle, and part of the atria (Brade et al., 2018). The posterior mesoderm and cardiac precursors produce ATRA, which at this stage is patterned in a caudo-rostral gradient determining the inflow-outflow poles of the heart tube (S. Wang & Moise, 2019). <h4>Specification Second Heart Field</h4> The SHF is specified by ISL1 (Islet-1, transcription factor and SHF specifier) positive cells and contributes to the sub-pulmonary myocardium (S. Wang & Moise, 2019). Higher levels of ATRA promote posterior precursors of the FHF and SHF committing to the inflow tract (Hochgreb et al., 2003; Niederreither et al., 2001; Ryckebusch et al., 2008a; Sirbu et al., 2008; S. Wang & Moise, 2019). Subsequently, ATRA restricts SHF boundaries and stimulates a SHF sublineage giving rise to the outflow tract (OFT) (P. Li et al., 2010; Ma et al., 2016; Nakajima, 2019; S. Wang & Moise, 2019). <h4>Heart tube looping / outflow tract development</h4> As the heart tube grows, looping will occur at E9 in mice (S. Wang & Moise, 2019). During this process the straight heart tube will be remodeled by forming a coiling loop to eventually form a multichambered heart. ATRA receptors (RARs) have been shown to be essential for cardiac looping, left-right patterning, and inflow tract development (Perl & Waxman, 2019). For proper OFT development in mice, Hox genes are necessary which are responsive to ATRA (Perl & Waxman, 2019). <h4>Chamber formation </h4> Chamber septation emerges at E10 in mice (S. Wang & Moise, 2019). Interaction of cardiomyocytes with epicardial, endocardial and cardiac neural crest cells (Brade et al., 2018). ATRA is needed for the posterior heart segment to become the primitive atrium and sinus venosus (Nakajima, 2019). At later stages, ATRA stimulates growth and maturation of the ventriculi (Nakajima, 2019). <h4>Proepicardium / Coronary vessel development</h4> The proepicardial cells are formed between E9.5 and E11.5 in mice, migrate from a location near the sinus venosus to cover the primitive heart tube, and will form the epicardium which is the outer layer of the heart (Brade et al., 2018; S. Wang & Moise, 2019). Mesenchymal subepicardial cells and epicardial derived cells will merge and differentiate to the coronary plexus around E11.5 in mice and subsequently coronary vessels form around the ventricle until E13.5 (Brade et al., 2018). Several lines of evidence indicate that precision in ATRA levels and timing is important in coronary vasculature development and are reviewed by Wang and Moise (S. Wang & Moise, 2019). Coronary vasculature defects resulting from perturbed ATRA homeostasis usually concurs with myocardial expansion, vasculature development and fetal erythropoiesis (S. Wang & Moise, 2019). <h4>myocardial expansion (ventricular wall expansion)</h4> The FHF contributes primarily to the myocardium (S. Wang & Moise, 2019). ATRA signaling in epicardial(-derived) cells stimulates a signal promoting myocardium growth (Brade et al., 2011; S. Wang & Moise, 2019). The embryonic liver is thought to contribute to myocardial expansion through erythropoietin (EPO) secretion, which is a direct target of ATRA in the liver, and in turn induces insulin growth factor 2 (IGF2) release from the epicardium (Brade et al., 2011; S. Wang & Moise, 2019). Inactivation of EPO or its receptor resulted in ventricular hypoplasia (S. Wang & Moise, 2019; Wu et al., 1999). <h4>Cardiac neural crest orientation and positioning </h4> Cardiac neural crest cells (cNCCs) mainly provide patterning signals that contribute to the aortic arteries, OFT/aortopulmonary development and septation, and formation of a functional myocardium (Brade et al., 2018; Stefanovic & Zaffran, 2017; S. Wang & Moise, 2019). Additionally, cNCCs contribute to the heart valves and parasympathetic innervation (Brade et al., 2018; Stefanovic & Zaffran, 2017; S. Wang & Moise, 2019). Furthermore, preotic cNCC derived precursors contribute to vascular smooth muscle cell formation and eventually to proximal coronary arteries (Stefanovic & Zaffran, 2017). ATRA influences the cNCC migration and differentiation, which contribute to the aorticopulmonary septum / OFT (el Robrini et al., 2016; Ma et al., 2016; S. Wang & Moise, 2019).

adjacent

Moderate

High adjacent

Low

High adjacent

Low

Moderate adjacent

Low

High

High Mixed

High

Fetal

High High Moderate

This AOP regarding ATRA homeostasis and cardiovascular development applies to both male and female sexes. The life stage in which the processes described as KEs and KERs are applicable is during fetal development. Strongest evidence on cardiovascular development regulation used to generate this AOP is from chicken and mouse studies with also some evidence from rat and zebrafish. Evidence exists that similar mechanisms are available in vertebrate species and therefore this AOP also applies to humans, although the evidence is not as strong.

The essentiality of each KE was determined by the impact of the upstream modified MIE or KE on the downstream KEs or AO. The level of support for essentiality of MIE and KEs within the overall AOP is high. <h6>MIE: RALDH inhibition</h6> The essentiality for the MIE is high because knockout and/or inhibition studies show perturbed ATRA concentrations (KE1), patterning defects in the second heart field (KE2), restricted contribution of neural crest cells (KE3), and various cardiovascular defects including transposition great arteries (AO). Indirect evidence for essentiality of the MIE was identified as a large impact on the MIE (i.e. knockout studies) associated with an increased frequency of the downstream AO of the transposition of the great arteries. Evidence from stressors for RALDH related to cardiovascular developmental defects is also available. For example, WIN18446 (or bis-(dichloroacetyl)diamine) is an irreversible RALDH inhibitor (RALDH1, -2, and -3), that also can cause abnormal development of the aortic arch and outflow tract, coronary arteries, and the myocardium and also it can cause syndromes as tetralogy of Fallot in rats, mice and chick (Fujino et al., 2005; Kise et al., 2005; Kuribayashi & Roberts, 1993; Nishijima et al., 2000; Okamoto et al., 2004; Okishima et al., 1992; Tasaka et al., 1991; S. Wang et al., 2018). RALDH2 is important for almost all ATRA synthesis in the heart as was shown by knockdown studies (Stefanovic & Zaffran, 2017). Mutations of the Raldh2 gene result in phenotypes characterized by prominent myocardial defects also resulting in embryonic lethality (Brade et al., 2011; el Robrini et al., 2016; Merki et al., 2005; Niederreither et al., 1999, 2001; Sorrell & Waxman, 2011; Stefanovic & Zaffran, 2017; S. Wang & Moise, 2019). Raldh2 null mice mutants that were rescued from embryo lethality showed abnormal cNCC migration (Niederreither et al., 2003). Rescued Raldh2 mouse mutant embryos also showed a disruption of the posterior limit of the SHF starting at E7.5 (Duong & Waxman, 2021; Ryckebusch et al., 2008a; Sirbu et al., 2008). Next to RALDH, other enzymes are also involved in the formation of ATRA but also in the breakdown of ATRA. <h6>KE1: ATRA concentration</h6> The essentiality for the KE of disturbed ATRA levels is high as it all affects KE2, KE3 and AO. Vertebrate embryo-fetal cardiovascular development involves multiple steps and great knowledge is available including the importance of all-trans retinoic acid (ATRA) which has been reviewed in multiple papers (Brade et al., 2018; Duong & Waxman, 2021; Nakajima, 2019; Perl & Waxman, 2019; Stefanovic & Zaffran, 2017; S. Wang & Moise, 2019). As different processes in embryodevelopment benefit from varying levels of ATRA, an ATRA gradient exists which is generated by multiple enzymes that synthesize and degrade ATRA to maintain the preferred balance (Kedishvili, 2013; Menegola et al., 2021; Tonk & Pennings, 2015). This gradient is important in SHF patterning (Nakajima, 2019). There is also some evidence that mutants of the retinoid receptor partially revealed the mechanism of cNCC involved in cardiovascular development (Kubalak et al., 2002). Vitamin A deficiency in embryos resulted in heart developmental defects such as septal defects, abnormalities to the inflow and outflow tract, aortic arch abnormalities and coronary malformations in quail and rat (Dersch & Zile, 1993; Heine et al., 1985; Wilson & Warkany, 1949, 1950). <h6>KE2: SHF patterning</h6> The essentiality is high for correct SHF patterning since different parts within the SHF are responsible for correct formation of the different anatomical positions in the developed heart as was reviewed by Nakajima in 2019 (Nakajima, 2019). Impaired development of the SHF causes cardiovascular developmental defects (Nakajima, 2019). <h6>KE3: cNCC contribution</h6> The contribution of cardiac neural crest cells to the development of the heart is highly essential because neural crest cell ablation studies show multiple cardiovascular developmental defects including transposed great arteries such as of the aortic arch (Plein et al., 2015). <h6>AO: transposition great arteries</h6> Normal cardiovascular development including normal patterning of the great arteries is essential as disruptions can lead to fetal death or teratogenic defects upon birth that hampers functioning of the newborn.

<h3><a name="_Toc95815320">Biological plausibility</a></h3> The overall biological plausibility of the AOP was assessed as high. The role for ALDH1A2 in the synthesis of ATRA is well established as an essential component of regulating regional ATRA expression during development. The role of ATRA within cardiovascular development is highly plausible including its involvement in SHF patterning and signaling, which is important for consequent predispositioning to specific anatomical parts/occurrences in cardiovascular development. After the initial patterning stages, the size of the cardiac progenitor pool is controlled within the anterior lateral plate mesoderm, ATRA signaling then divides the anterior and posterior SHFs (Keegan et al., 2005; S. Wang & Moise, 2019). High ATRA signaling defines the posterior boundary of the murine second heart field (Ryckebusch et al., 2008a; Sirbu et al., 2008). This is exemplified by the ATRA producing enzyme RALDH, which is expressed in posterior SHF progenitors in mice (Stefanovic et al., 2020). The biological plausibility of the relationship between SHF signaling and cNCC contribution is moderate because the relationship between the two KEs still contain unknowns in terms of mechanistic connections. Additionally, there is an interdependent relationship between the SHF and cNCC, but also the pharyngeal endoderm plays an indispensable role in this tripartite connection (Diman et al., 2011). There is strong biological plausibility for a link between ATRA synthesis and normal positioning of the great arteries during early development, mainly determined by mouse RALDH knouckout studies. Because of evolutionary consistencies between vertebrates (Pérez-Pomares et al., 2009), the relationship is regarded biologically plausible also in humans. No direct human evidence is available and therefore the weight of evidence is not as strong.  <h6>Empirical evidence</h6> Dose-concordance The quantitative understanding of dose-response relationships is limited in this AOP. 0.25-0.5 mg/ml ATRA administration specific to the anterior heart field using beads in chick embryo culture, resulted in disturbed SHF specific gene expression levels and transposition of the great arteries (Narematsu et al., 2015). ATRA is a morphogen and the required ATRA levels are dependent on the location within the fetus for patterning and varies depending on the developmental stage (Piersma et al., 2017). Temporal-concordance The temporal sequence of events is strong as they are based on the biological process that are taking place. The critical period for chemical perturbations that apply to this AOP is during fetal life. The sequence in time starts with inhibition of RALDH leading to reduced ATRA synthesis. Consequently, the ATRA gradient in the SHF is disrupted resulting in an impaired pattering of the progenitors within the SHF. The progenitors within the SHF differ in signaling properties and an impaired progenitor patterning also impairs signaling to the cNCCs, which in turn fail to contribute to correct great artery development. The relationship between the SHF and cNCC occurs at similar timepoints as they are interdependent and at the same time also communicate with the pharyngeal endoderm to be able to contribute to cardiovascular development. Uncertainties In mice, there is strong evidence to support the view that ATRA is important in cardiovascular development including the positioning of the great arteries. Evidence from RALDH knockout studies is also consistent. The migration and development of cNCCs not solely depends on SHF signaling. The pharyngeal endoderm also plays an important role in the maintenance and deployment of cNCCs through signaling of sonic hedgehog (Shh) (Goddeeris et al., 2007; Vincent & Buckingham, 2010). In the absence of Shh, the development of proper pharyngeal arches and OFT is affected (Vincent & Buckingham, 2010). Additionally, a possible feedback loop exists between SHF signaling to cNCCs, since ablation of cNCCs results in SHF over proliferation because of excessive Fgf8 signaling (Rochais et al., 2009). Furthermore, NCC deletion of Smad4 leads to abnormal SHF patterning and a shorter OFT. Lastly, Tbx3 loss in NCCs and pharyngeal endoderm also resulted in SHF over proliferation and a shorter OFT (Rochais et al., 2009).

This AOP is of qualitative understanding. Quantitative data between chemical potency and perturbations are insufficient. This relates to the mainly strong evidence of the MIE coming from gene knockout studies. Furthermore, ATRA is a morphogen and the required ATRA levels are dependent on the location within the fetus for patterning and varies depending on the developmental stage (Piersma et al., 2017).

Not Specified

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Development, 126(16), 3597–3605. https://doi.org/10.1242/DEV.126.16.3597   AOPWiki 2022-01-27T11:16:35

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