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

Vid Modic^1,2, Roman Li³, Ziva Ramsak², Colette vom Berg³, Anze Zupanic^2,3

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

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. 

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.

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