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Relationship: 2404

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

Overexpression of rasl11b leads to Decrease, Cell proliferation

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Overexpression of rasl11b

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Decrease, Cell proliferation

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	Vid Modic (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

Ras proteins are well known to be involved in the mitogen-activated protein kinase (MAPK) pathway, therefore, it is hypothesized that Rasl11b acts as a negative regulator of MAPK by outcompeting Ras for its effectors such as Raf, leading to decreases in retinal progenitor cells (RPCs) proliferation seen in morphant embryos (Emerson et al., 2017).

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

Rasl11b is a member of the small GTPase protein family with a high degree of similarity to RAS proteins (Stolle et al., 2007). Orthologous to human RASL11B (RAS like family 11 member B) (ZFIN Gene: Rasl11b, n.d.). The Rasl11b protein is highly conserved among vertebrates, sharing on average 94% homology with its mammalian orthologues (Pézeron et al., 2008).

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

It is hypothesized that Rasl11b acts as a negative regulator of MAPK by outcompeting Ras for its effectors such as Raf. After the overexpression of rasl11b, G0/G1 phase cell cycle arrest is induced and the proliferation of RPCs is inhibited (Emerson et al., 2017; He et al., 2018).

To determine if increased rasl11b expression contributes to decreased proliferation of RPCs, single-cell zebrafish embryos were injected with full-length rasl11b mRNA. Proliferation (pHH3) was visualized in the early eye field (rx3:GFP) of 18 somite embryos injected with 200 pg or 400 pg rasl11b mRNA. Overexpression of rasl11b resulted in decreased RPC proliferation in a dose-dependent manner. At 48 hpf, overexpression of rasl11b resulted in smaller eyes. (Emerson et al., 2017) show that rasl11b is negatively regulated downstream of Sema6a/Plxna2 signaling and when overexpressed, decreases RPC proliferation and eye size.
(Emerson et al., 2017) confirmed through morpholino knockdown, that Sema6a/Plxna2 signaling regulates proliferation and cohesive migration of RPCs in developing optic vesicles in zebrafish. Initial characterization of one gene, rasl11b, uncovered its contributing role to the proliferation of RPCs, providing insight into the mechanisms that control this key developmental process.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

No data.

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.

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. 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

No data.

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

The relationships described herein have been primarily established in zebrafish models (Emerson et al., 2017). Evidence is also provided for humans (He et al., 2018). Because rasl11b protein is highly conserved among vertebrates, sharing on average 94% homology with its mammalian orthologues this KE relationship could be translated to other vertebrates and mammals.

References

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

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. (2017a). Identification of target genes downstream of semaphorin6A/PlexinA2 signaling in zebrafish. Developmental Dynamics, 246(7), 539–549. https://doi.org/10.1002/dvdy.24512

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

Pézeron, G., Lambert, G., Dickmeis, T., Strä Hle, U., Dé, F., Rosa, R. M., & Mourrain, P. (2008). Rasl11b Knock Down in Zebrafish Suppresses One-Eyed-Pinhead Mutant Phenotype. PLoS ONE. https://doi.org/10.1371/journal.pone.0001434

Stolle, K., Schnoor, M., Fuellen, G., Spitzer, M., Cullen, P., & Lorkowski, S. (2007). Cloning, genomic organization, and tissue-specific expression of the RASL11B gene. Biochimica et Biophysica Acta - Gene Structure and Expression, 1769(7–8), 514–524. https://doi.org/10.1016/j.bbaexp.2007.05.005

ZFIN Gene: rasl11b. (n.d.). Retrieved March 19, 2021, from http://zfin.org/ZDB-GENE-040426-793