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Relationship: 2079

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

Inhibition, Activin signaling leads to Inhibition, Fin regeneration

Upstream event

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

Inhibition, Activin signaling

Downstream event

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

Inhibition, Fin regeneration

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
Glucocorticoid Receptor Agonism Leading to Impaired Fin Regeneration	adjacent	High		Alexander Cole (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
teleost fish	teleost fish		NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Mixed

Life Stage Applicability

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

Term	Evidence
All life stages

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

Activin is a dimeric protein composed of two β subunits. These subunits – either β_A or β_B – dictate the specific type of activin depending on their pairing. Activins have different function depending on the tissue in which they are acting (Kaneko, 2016) Activin plays a large role in cancer metastasis, immune response, inflammation and cell migration (Kang & Shyr, 2011). Fin regeneration is a naturally occurring process in fish (Fu et al., 2013). Fin regeneration is a complex process involving coordinated cellular processes such as cellular signaling, differentiation, and migration .Activin is known to play a large role in the promotion of blastemal cell proliferation during the fin regeneration process (Wehner & Weidinger, 2015).

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

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

Activin plays a large role in cancer metastasis, immune response, inflammation and cell migration (Kang & Shyr, 2011).
The activin signaling pathway is involved with the promotion of blastemal cell proliferation and the cell migration during the formation of the wound epidermis, a crucial point the fin regeneration process (Wehner & Weidinger, 2015).
With Activin signaling inhibited, the lack of cell migration would lead to a failure or delay in the formation the wound epidermis. This may impair the downstream processes and result in impaired fin regeneration.

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

Activin signaling has been found to be crucial in fin regeneration. Larval zebrafish exposed to 100µM SB431542, a known inhibitor of Activin and TGF-β signaling, showed complete inhibition of fin regeneration 72 hours post amputation (Garland et al., 2019).
Jaźwińska et al. (2007) previously exposed adult zebrafish to SB431542 at 10µM and SB505124 at 2µM post amputation and saw impaired fin regeneration.
A morpholino knockdown of activin-βA and its receptor, alk4, also significantly impaired fin regeneration (Jaźwińska et al., 2007).

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

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

Not yet evaluated.

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

Data to characterize the quantitative relationship between GR activation and cripto-1 express is currently lacking.

Response-response Relationship

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

Not yet evaluated.

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

Not yet evaluated.

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

Not yet evaluated.

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 function of activin is well conserved across species (Hinck, 2012). In ray-finned fish (teleost), the regeneration of fins is naturally occuring (Fu et al., 2013). Activin plays a large role in the migration of cells during this process (Wehner & Weidinger, 2015). Therefore, it can be assumed that the inhibition of activin leading to an inhibition of fin regeneration is consistent across teleost.

References

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

Fu C, Cao ZD, Fu SJ. 2013. The effects of caudal fin loss and regeneration on the swimming performance of three cyprinid fish species with different swimming capacities. The Journal of Experimental Biology 216:3164-3174. doi:10.1242/jeb.084244

Garland MA, Sengupta S, Mathew LK, Truong L, Jong ED, Piersma AH, Du JL, Tanguay RL. 2019. Glucocorticoid receptor-dependent induction of cripto-1 (one-eyed pinhead) inhibits zebrafish caudal fin regeneration. Toxicology Reports 6:529-537. https://doi.org/10.1016/j.toxrep.2019.05.013

Jaźwińska A, Badakov R, Keating MT. 2007. Activin-βA Signaling is Required for Zebrafish Fin Regeneration. Current Biology 17:1390-1395. DOI 10.1016/j.cub.2007.07.019

Kaneko H, 2016. Handbook of Hormones: Pages 295-297, e33B-2.

Kang HY, Shyr CR. 2011. Activins and Cell Migration. Vitamins and Hormons 85: 129-48. doi: 10.1016/B978-0-12-385961-7.00007-X.

Wehner D, Weidinger G. 2015. Signaling networks organizing regenerative growth of the zebrafish fin. Trends in Genetics 31 (6):336-343. http://dx.doi.org/10.1016/j.tig.2015.03.012