Aop: 399

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Inhibition of Fyna leading to increased mortality via decreased eye size (Microphthalmos)

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Inhibition of Fyna leading to increased mortality

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Vid Modic1,2, Roman Li3, Ziva Ramsak2, Colette vom Berg3, Anze Zupanic2,3

1University of Ljubljana, Faculty of Chemistry and Chemical Technology, Večna pot 113, Ljubljana, Slovenia

2National Institute of Biology, Večna pot 111, Ljubljana, Slovenia

3Eawag - Swiss Federal Institute of Aquatic Science and Technology, Ueberlandstrasse 133, Duebendorf, Switzerland

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Vid Modic   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Vid Modic
  • Anze Zupanic

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Open for citation & comment
This AOP was last modified on January 13, 2022 07:32

Revision dates for related pages

Page Revision Date/Time
Inhibition of Fyna December 12, 2021 12:07
Inhibition of Plxna2 October 07, 2021 13:43
Overexpression of rasl11b December 08, 2021 11:47
Decrease, Cell proliferation December 07, 2020 06:55
Decreased, Eye size June 24, 2021 13:59
Increased Mortality July 08, 2022 07:32
Decrease, Population growth rate July 08, 2022 07:40
Altered, Visual function July 08, 2022 07:30
Inhibition of Fyna leads to Inhibition of Plxna2 December 12, 2021 16:31
Inhibition of Plxna2 leads to Overexpression of rasl11b December 12, 2021 16:34
Overexpression of rasl11b leads to Decrease, Cell proliferation December 12, 2021 16:40
Decrease, Cell proliferation leads to Decreased, Eye size August 07, 2021 13:43
Decreased, Eye size leads to Altered, Visual function January 07, 2022 13:41
Altered, Visual function leads to Increased Mortality July 08, 2022 08:26
Increased Mortality leads to Decrease, Population growth rate July 08, 2022 08:29
Rosmarinic acid May 28, 2021 07:40
Saracatinib May 28, 2021 08:09
Staurosporine May 28, 2021 08:17

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This AOP starts with inhibition of Fyna (Src family tyrosine kinase A) activity and leads to increased mortality (AO) via reduced eye size (microphthalmos). Inhibition of Fyna activity is defined as the molecular initiating event (MIE) that leads to reduction in Plxna2 phosphatase activity (KE1). Reduction in Plxna2 activity leads to overexpression of rasl11b (KE2). Increased levels of Rasl11b cause reduction of cell proliferation in the developing eye (KE3). Reduced cell proliferation in the developing eye leads to reduced eye size (KE4) which in turn leads to altered visual function (KE5). It is in some cases accompanied with severe eye deformation which can lead to increase in mortality for the individual. Fyna can be inhibited by pharmaceuticals, such as Saracatinib, Mastinib, Staurosporine and Rosmarinic acid, as has been shown in several in vitro studies. As Fyna kinase inhibition is being intensively studied in the fields of Alzheimer's disease and anti-inflammatory therapy, the use of the inhibitors has the potential to significantly increase in the following decades. The key events described in this AOP were mostly studied in Zebrafish (Danio rerio) but can be theoretically transferred to other vertebrates as the involved genes are highly similar among vertebrates. 

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

The motivation behind building the AOP was methodological. Our team has recently developed molecular causal networks for developmental cardiotoxicity and neurotoxicity in zebrafish (doi.org/10.1021/acs.chemrestox.0c00095). These networks are highly curated, but rather large, going from adverse outcomes on the organ level upstream to wherever evidence takes us (many times finishing at what would be called MIEs). As there are many causal networks already present on the http://causalbionet.com/ (mostly for humans and for lung conditions), we were wondering how the rich knowledge available in causal pathways could be translated to AOPs. The AOP described in this document is one such example. 

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1884 Inhibition of Fyna Inhibition of Fyna
KE 1885 Inhibition of Plxna2 Inhibition of Plxna2
KE 1886 Overexpression of rasl11b Overexpression of rasl11b
KE 1821 Decrease, Cell proliferation Decrease, Cell proliferation
KE 1878 Decreased, Eye size Decreased, Eye size
KE 1643 Altered, Visual function Altered, Visual function
AO 351 Increased Mortality Increased Mortality
AO 360 Decrease, Population growth rate Decrease, Population growth rate

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
During brain development High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
zebrafish Danio rerio High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

An overall assessment of this AOP shows that there is moderate biological plausibility to support a qualitative link between the Fyna kinase inhibition to the KE5 of altered visual function and high evidence linking KE5 to decreased population trajectory. Biological plausibility is considered moderate because there is ample evidence from gain- and loss- of function experiments and knock out animal models that support the relationships between key events and are consistent with current biological knowledge. A score of high in this respect would require further evidence for chemical inhibition or experimental downregulation of zebrafish Fyna kinase and direct or more extensive evidence linking Plxna2 inhibition to rasl11b overexpression. The evidence for essentiality of the KEs is mostly missing therefore the overall assessment of essentiality is low. The same goes for empirical support, currently there is no evidence for empirical support. Additional studies are needed to obtain data for empirical support, therefore, the empirical support of KERs is considered is low.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Life stage: The current AOP is applicable from minutes after fertilization (0 hpf) and up to end of gastrulation phase (~10.33 hpf) (Rongish & Kinsey, 2000). After gastrulation phase Fyna kinase is not bserved in developing zebrafish and inhibition of Fyna kinase is not applicable.

Taxonomic: This AOP is  based on experimental evidence from studies on zebrafish, but is potentially also relevant to other vertebrates, because of conservation of all involved key events  (Fyna activation, Sema/Plxna signaling, Rasl11b, Eye development).

Sex: Sex differences are typically not investigated in tests using early life stages of zebrafish and it is currently unclear whether sex-related differences are important in this AOP.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help
Support for Essentiality of KEs

Defining Question: Are downstream KEs and/or the AO prevented if an upstream KE is blocked?

  • High (Strong): Direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important KEs (e.g. stop/reversibility studies, antagonism, knock out models, etc.).
  • Moderate: Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE leading to increase in KE down or AO.
  • Low (Weak): No or contradictory experimental evidence of the essentiality of any of the KEs.
MIE: Inhibition of Fyna Low: No experimental evidence of essentiality.
KE1: Inhibition of Plxna2 Moderate: reduced eye size phenotype can be rescued by plxna2 activation (St Clair et al., 2018).
KE2: Overexpression of rasl11b Low: No experimental evidence of essentiality.
KE3: Decreased  cell proliferation Low: No experimental evidence of essentiality.
KE4: Decreased eye size Low: No experimental evidence of essentiality.
KE5: Altered visual function Low: No experimental evidence of essentiality.
AO: Increased  mortality High: Inability to perceive the environment leads to increase in mortality (Dehnert et al., 2019; Besson et al., 2020).
AO: Decrease of  population trajectory High: decrease in population trajectory is an imminent result of increased mortality (Rearick et al., 2018).

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help
Support for Biological Plausibility of KERs

Defining Question: Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge?

  • High (Strong): Extensive understanding of the KER based on extensive previous documentation and broad acceptance.
  • Moderate: KER is plausible based on analogy to accepted biological relationships, but scientific understanding is incomplete.
  • Low (Weak): Empirical support for association between KEs, but the structural or functional relationship between them is not understood.
KER1: Inhibition of Fyna leads to inhibition of Plxna2 Moderate: Extensive understanding of Fyna phosphorylating activity and consequent changes in Plxna2 signalization, but there is currently no data on chemical inhibition of zebrafish Fyna kinase.
KER2: Inhibition of Plxna2 leads to overexpression of rasl11b Low: There is missing direct evidence for the relationship and poor functional and structural understanding of interactions
KER3: Overexpression of rasl11b leads decreased cell proliferation High: Impact of Rasl11b on cell proliferation is well understood across different taxonomic groups.
KER4: Decreased cell proliferation leads to decreased eye size High: Extensive understanding that decreased proliferation of RPCs leads to decreased eye size.
KER5: Decreased eye size leads to altered Visual function High: Extensive understanding that changes in eye size greatly effect visual function
KER6: Altered visual function leads to increased mortality High: Extensive understanding that defective visual function greatly increases the chance of death due to various factors
KER7: Increased mortality leads to decrease of population trajectory High: Extensive understanding that increased mortality on individual level decreases population trajectory

Empirical support: Currently there is no sufficient evidence to estimate the weight of the evidence of empirical support for KERs in this AOP. Further more specific research on the relationships between the entities involved in the AOP is needed.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Data to support the quantitative understanding of this AOP is currently lacking.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

Babkiewicz, E., Bazała, M., Urban, P., Maszczyk, P., Markowska, M., & Maciej Gliwicz, Z. (2020). The effects of temperature on the proxies of visual detection of Danio rerio larvae: observations from the optic tectum. https://doi.org/10.1242/bio.047779

Besson, M., Feeney, W. E., Moniz, I., François, L., Brooker, R. M., Holzer, G., Metian, M., Roux, N., Laudet, V., & Lecchini, D. (n.d.). Anthropogenic stressors impact fish sensory development and survival via thyroid disruption. https://doi.org/10.1038/s41467-020-17450-8

Challa, A. K., & Chatti, K. (2013). Conservation and Early Expression of Zebrafish Tyrosine Kinases Support the Utility of Zebrafish as a Model for Tyrosine Kinase Biology. 10(3). https://doi.org/10.1089/zeb.2012.0781

Corral-López, A., Garate-Olaizola, M., Buechel, S. D., Kolm, N., & Kotrschal, A. (2017). On the role of body size, brain size, and eye size in visual acuity. Behavioral Ecology and Sociobiology, 71(12). https://doi.org/10.1007/s00265-017-2408-z

Dehnert, G. K., Karasov, W. H., & Wolman, M. A. (2019). 2,4-Dichlorophenoxyacetic acid containing herbicide impairs essential visually guided behaviors of larval fish. Aquatic Toxicology, 209(October 2018), 1–12. https://doi.org/10.1016/j.aquatox.2019.01.015

Emerson, S. E., St. Clair, R. M., Waldron, A. L., Bruno, S. R., Duong, A., Driscoll, H. E., Ballif, B. A., McFarlane, S., & Ebert, A. M. (2017). Identification of target genes downstream of semaphorin6A/PlexinA2 signaling in zebrafish. Developmental Dynamics, 246(7), 539–549. https://doi.org/10.1002/dvdy.24512

Franco, M., & Luca Tamagnone, &. (2008). Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive. EMBO Reports, 9, 865–871. https://doi.org/10.1038/embor.2008.139

Green, T. P., Fennell, M., Whittaker, R., Curwen, J., Jacobs, V., Allen, J., Logie, A., Hargreaves, J., Hickinson, D. M., Wilkinson, R. W., Elvin, P., Boyer, B., Carragher, N., Plé, P. A., Bermingham, A., Holdgate, G. A., Ward, W. H. J., Hennequin, L. F., Davies, B. R., & Costello, G. F. (2009). Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. Molecular Oncology, 3(3), 248–261. https://doi.org/10.1016/j.molonc.2009.01.002

He, H., Dai, J., Zhuo, R., Zhao, J., Wang, H., Sun, F., Zhu, Y., & Xu, D. (2018). Study on the mechanism behind lncRNA MEG3 affecting clear cell renal cell carcinoma by regulating miR-7/RASL11B signaling. Journal of Cellular Physiology, 233(12), 9503–9515. https://doi.org/10.1002/jcp.26849

Kennedy, B. N., Stearns, G. W., Smyth, V. A., Ramamurthy, V., Van Eeden, F., Ankoudinova, I., Raible, D., Hurley, J. B., & Brockerhoff, S. E. (2004). Zebrafish rx3 and mab21l2 are required during eye morphogenesis. Developmental Biology, 270(2), 336–349. https://doi.org/10.1016/j.ydbio.2004.02.026

Le, H. G., Dowling, J. E., & Cameron, D. J. (2012). Early retinoic acid deprivation in developing zebrafish results in microphthalmia. Visual Neuroscience, 29(4–5), 219–228. https://doi.org/10.1017/S0952523812000296

Nygaard, H. B., Van Dyck, C. H., & Strittmatter, S. M. (2014). Fyn kinase inhibition as a novel therapy for Alzheimer’s disease. Alzheimer’s Research and Therapy, 6(1), 1–8. https://doi.org/10.1186/alzrt238

Rongish BJ, Kinsey WH. Transient nuclear localization of Fyn kinase during development in zebrafish. Anat Rec. 2000 Oct 1;260(2):115-23. doi: 10.1002/1097-0185(20001001)260:2<115::AID-AR10>3.0.CO;2-C. PMID: 10993948.

Sasaki, Y., Cheng, C., Uchida, Y., Nakajima, O., Ohshima, T., Yagi, T., Taniguchi, M., Nakayama, T., Kishida, R., Kudo, Y., Ohno, S., Nakamura, F., & Goshima, Y. (2002). Fyn and Cdk5 Mediate Semaphorin-3A Signaling, Which Is Involved in Regulation of Dendrite Orientation in Cerebral Cortex drite guidance in the cerebral cortex. We propose a signal transduction pathway in which Fyn and Cdk5 mediate neuronal guidance regula. Neuron, 35, 907–920.