This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Inhibition of Fyna leading to increased mortality via decreased eye size (Microphthalmos)
Point of Contact
- Vid Modic
- Anze Zupanic
|Author status||OECD status||OECD project||SAAOP status|
|Open for citation & comment|
This AOP was last modified on January 13, 2022 07:32
|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||September 08, 2021 07:07|
|Decrease, Population growth rate||May 26, 2022 16:04|
|Altered, Visual function||June 16, 2022 07:36|
|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||January 13, 2022 07:31|
|Increased Mortality leads to Decrease, Population growth rate||December 10, 2021 04:03|
|Rosmarinic acid||May 28, 2021 07:40|
|Saracatinib||May 28, 2021 08:09|
|Staurosporine||May 28, 2021 08:17|
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.
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.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Sequence||Type||Event ID||Title||Short name|
|1||MIE||1884||Inhibition of Fyna||Inhibition of Fyna|
|2||KE||1885||Inhibition of Plxna2||Inhibition of Plxna2|
|3||KE||1886||Overexpression of rasl11b||Overexpression of rasl11b|
|4||KE||1821||Decrease, Cell proliferation||Decrease, Cell proliferation|
|5||KE||1878||Decreased, Eye size||Decreased, Eye size|
|6||KE||1643||Altered, Visual function||Altered, Visual function|
Relationships Between Two Key Events (Including MIEs and AOs)
|Inhibition of Fyna leads to Inhibition of Plxna2||adjacent||Moderate||Low|
|Inhibition of Plxna2 leads to Overexpression of rasl11b||adjacent||Low||Low|
|Overexpression of rasl11b leads to Decrease, Cell proliferation||adjacent||High||Low|
|Decrease, Cell proliferation leads to Decreased, Eye size||adjacent||High||Low|
|Decreased, Eye size leads to Altered, Visual function||adjacent|
|Altered, Visual function leads to Increased Mortality||adjacent|
|Increased Mortality leads to Decrease, Population growth rate||adjacent||High||High|
Life Stage Applicability
|During brain development||High|
Overall Assessment of the AOP
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
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
|Support for Essentiality of KEs||
Defining Question: Are downstream KEs and/or the AO prevented if an upstream KE is blocked?
|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).|
|Support for Biological Plausibility of KERs||
Defining Question: Is there a mechanistic relationship between KEup and KEdown consistent with established biological knowledge?
|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.
Data to support the quantitative understanding of this AOP is currently lacking.
Considerations for Potential Applications of the AOP (optional)
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