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Relationship: 2405
Title
Decrease, Cell proliferation leads to Decreased, Eye size
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Inhibition of Fyna leading to increased mortality via decreased eye size (Microphthalmos) | adjacent | High | Low | Brendan Ferreri-Hanberry (send email) | Open for citation & comment |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
zebrafish | Danio rerio | High | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | High |
Life Stage Applicability
Term | Evidence |
---|---|
Larvae | High |
Key Event Relationship Description
Decrease in proliferation of retinal progenitor cells (RPCs) results in decreased eye size.
Evidence Collection Strategy
Evidence Supporting this KER
Decrease in eye size due to teratogenic insult or genetic abnormalities may result from a number of different mechanisms, including general developmental delay, increased cell death, decreased cell proliferation, or decreased retinal cell differentiation (Stenkamp et al., 2002).
Biological Plausibility
Cell proliferation during retinal development adds volume to the eye, decrease of cell proliferation thus leads to decrease of eye volume.
Some studies showed that changes in different genes lead to decreased eye size:
- In zebrafish Rasl11b is negatively regulated downstream of Sema6A/Plxna2. To achieve rasl11b overexpression 200 pg or 400 pg full-length zebrafish rasl11b mRNA was injected into single-cell embryos. At 48 hpf, overexpression of rasl11b resulted in reduced cell proliferation of RPC and consequently in smaller eyes (Emerson et al., 2017).
- Zebrafish/mouse heterozygous knockouts of rx3 (retinal homeobox gene 3) have an eyeless phenotype (Graw, 2010; Muranishi et al., 2012; Tucker et al., 2001). This gene acts upstream of or within animal organ development and cell fate specification and is critical for survival of progenitor cells during eye morphogenesis (Kennedy et al., 2004).
- In mice Vsx2 gene is involved in neural retina development. Mice with impaired Vsx2 production have a small eye phenotype due to decreased proliferation of RPCs (Burmeister et al., 1996; Zagozewski et al., 2014).
Empirical Evidence
No data.
Uncertainties and Inconsistencies
No data.
Known modulating factors
No data.
Quantitative Understanding of the Linkage
No data.
Response-response Relationship
No data.
Time-scale
The period from 16 to 36 hr post fertilization (hpf) comprises two phases; during the first (16–27 hpf) the optic vesicle becomes the eye cup, and during the second (27–36 hpf) the eye cup begins to differentiate into the neural retina and pigmented epithelium. All cells in the eye primordium are proliferative prior to 28 hpf, and the length of the cell cycle has been estimated to be 10 hr at 24–28 hpf (Li, Hu, et al., 2000).
Known Feedforward/Feedback loops influencing this KER
No data.
Domain of Applicability
Evidence was provided for Zebrafish (Emerson et al., 2017; Harding et al., 2021; Kashyap et al., 2008; Le et al., 2012), mice (Graw, 2019; Harding et al., 2021), Xenopus (Graw, 2010; Mathers et al., 1997) and humans (Harding & Moosajee, 2019; Verma & Fitzpatrick, 2007; Warburg, 1993).
References
Burmeister, M., Novak, J., Liang, M. Y., Basu, S., Ploder, L., Hawes, N. L., Vidgen, D., Hoover, F., Goldman, D., Kalnins, V. I., Roderick, T. H., Taylor, B. A., Hankin, M. H., & McInnes, R. R. (1996). Ocular retardation mouse caused by Chx10 homeobox null allele: Impaired retinal progenitor proliferation and bipolar cell differentiation. Nature Genetics, 12(4), 376–384. https://doi.org/10.1038/ng0496-376
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
Graw, J. (2010). Eye development. Current Topics in Developmental Biology, 90(C), 343–386. https://doi.org/10.1016/S0070-2153(10)90010-0
Graw, J. (2019). Mouse models for microphthalmia, anophthalmia and cataracts. 138, 1007–1018. https://doi.org/10.1007/s00439-019-01995-w
Harding, P., Lima Cunha, D., & Moosajee, M. (2021). Animal and cellular models of microphthalmia. Ther Adv Rare Dis, 2, 1–34. https://doi.org/10.1177/2633004021997447
Harding, P., & Moosajee, M. (2019). The Molecular Basis of Human Anophthalmia and Microphthalmia. J. Dev. Biol., 7(16). https://doi.org/10.3390/jdb7030016
Kashyap, B., Frederickson, L. C., & Stenkamp, D. L. (2008). Mechanisms for persistent microphthalmia following ethanol exposure during retinal neurogenesis in zebrafish embryos. Visual Neuroscience, 24(3), 409–421. https://doi.org/10.1017/S0952523807070423
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
Li, Z., Hu, M., Ochocinska, M. J., Joseph, N. M., & Easter, S. S. (2000). Modulation of Cell Proliferation in the Embryonic Retina of Zebrafish (Danio rerio). Developmental Dynamics, 219(3), 391–401.
Li, Z., Joseph, N. M., & Easter, S. S. (2000). The Morphogenesis of the Zebrafish Eye, Including a Fate Map of the Optic Vesicle.
Mathers, P. H., Grinberg, A., Mahon, K. A., & Jamrich, M. (1997). The Rx homeobox gene is essential for vertebrate eye development. Nature, 387(6633), 603–607. https://doi.org/10.1038/42475
Muranishi, Y., Terada, K., & Furukawa, T. (2012). An essential role for Rax in retina and neuroendocrine system development. Dev. Growth Differ., 54, 341–348. https://doi.org/10.1111/j.1440-169X.2012.01337.x
Stenkamp, D. L., Frey, R. A., Mallory, D. E., & Shupe, E. E. (2002). Embryonic Retinal Gene Expression in Sonic-You Mutant Zebrafish. Developmental Dynamics, 225, 344–350. https://doi.org/10.1002/dvdy.10165
Tucker, P., Laemle, L., Munson, A., Kanekar, S., Oliver, E. R., Brown, N., Schlecht, H., Vetter, M., & Glaser, T. (2001). The eyeless mouse mutation (ey1) removes an alternative start codon from the Rx/rax homeobox gene. Genesis, 31(1), 43–53. https://doi.org/10.1002/gene.10003
Verma, A. S., & Fitzpatrick, D. R. (2007). Anophthalmia and microphthalmia. Orphanet Journal of Rare Diseases, 2, 47. https://doi.org/10.1186/1750-1172-2-47
Warburg, M. (1993). Classification of microphthalmos and coloboma. Journal of Medical Genetics, 30(8), 664–669. https://doi.org/10.1136/jmg.30.8.664
Zagozewski, J. L., Zhang, Q., & Eisenstat, D. D. (2014). Genetic regulation of vertebrate eye development. Clinical Genetics, 86(5), 453–460. https://doi.org/10.1111/cge.12493
ZFIN Gene: vsx2. (n.d.). Retrieved March 27, 2021, from http://zfin.org/ZDB-GENE-001222-1