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Relationship: 2405

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Decrease, Cell proliferation leads to Decreased, Eye size

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
zebrafish Danio rerio High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Larvae High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Decrease in proliferation of retinal progenitor cells (RPCs) results in decreased eye size.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

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
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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).
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

No data.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

No data.

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

No data.

Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

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
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

No data.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

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

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

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