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|
|Under development: Not open for comment. Do not cite|
This AOP was last modified on July 21, 2021 16:26
|Inhibition of Fyna||July 15, 2021 09:42|
|Inhibition of Plxna2||July 15, 2021 10:32|
|Increase, Overexpression of rasl11b||June 07, 2021 03:03|
|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 trajectory||September 03, 2021 11:24|
|Altered, Visual function||September 16, 2021 06:19|
|Inhibition of Fyna leads to Inhibition of Plxna2||August 08, 2021 15:08|
|Inhibition of Plxna2 leads to Overexpression of rasl11b||July 15, 2021 10:42|
|Overexpression of rasl11b leads to Decrease, Cell proliferation||August 19, 2021 13:13|
|Decrease, Cell proliferation leads to Decreased, Eye size||August 07, 2021 13:43|
|Decreased, Eye size leads to Altered, Visual function||June 16, 2021 07:27|
|Altered, Visual function leads to Increased Mortality||August 24, 2021 05:25|
|Increased Mortality leads to Decrease, Population trajectory||September 03, 2021 12:08|
|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 studies 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||Increase, 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||Moderate||Low|
|Overexpression of rasl11b leads to Decrease, Cell proliferation||adjacent||Moderate||Low|
|Decrease, Cell proliferation leads to Decreased, Eye size||adjacent||Moderate||Low|
|Decreased, Eye size leads to Altered, Visual function||adjacent|
|Altered, Visual function leads to Increased Mortality||adjacent|
|Increased Mortality leads to Decrease, Population trajectory||adjacent||High||High|
Life Stage Applicability
Overall Assessment of the AOP
The focus of this AOP is on inhibition of the Fyna kinase that leads to defects in the developing eye of zebrafish. An overall assessment of this AOP shows that there is moderate biological plausibility and moderate empirical evidence to suggest a qualitative link between the Fyna kinase inhibition to the KE5 of altered visual function and high evidence linking KE5 to decreased population trajectory.
Domain of Applicability
Life stage: The current AOP is applicable from the segmentation period and up to larvae development of the zebrafish (10.33 hours psot fertilization – 30 days post fertilization.
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
While there is some evidence that suggests that the key events of this AOP are essential, further direct and indirect measurements would be neccessary to confirm this.
Data to support the quantitative understanding of this AOP is currently lacking.
Considerations for Potential Applications of the AOP (optional)
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
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.