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Relationship: 2485

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

GSK3beta inactivation leads to Repression of Gbx2 expression

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
GSK3beta inactivation leading to increased mortality via defects in developing inner ear 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
zebra fish Danio rerio High NCBI
human Homo sapiens 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
All life stages 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

Wnt signaling is implicated in anteroposterior (AP) axis patterning and midbrain specification in both animal and human systems. GSK3 is a key enzyme mediating the canonical Wnt signaling. Inhibition of GSK3b (one of the isoforms of GSK3) leads to activation of canonical Wnt signal pathway (Grassilli et al., 2014). Gbx2 is one of the representative AP markers and is downregulated in activation of Wnt signal pathway (GSK3b inhibition) (Kim et al., 2018).

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
  • Zebrafish embryos were treated with chemical inhibitors or activators of various signaling pathways, such as the Wnt, FGF, retinoic acid (RA), HH, BMP, Nodal, and Notch pathways, from 14 hpf to 18 hpf, immediately before the advent of gbx2 expression in the telencephalon, and than gbx2 expression was examined in the telencephalon. In  zebrafish embryos treated with BIO, a selective GSK3 inhibitor that activates Wnt signaling, gbx2 expression was specifically repressed in the telencephalon, but was unaffected or weakly activated in the isthmus and OV (Wang et al., 2018).
  • Treatment of human ESC-derived NCPs with BIO (Gsk3b inhibitor) downregulated expression of GBX2 in dose dependent manner (Kim et al., 2018). Quantitative gene expression analysis following seven days of treatment revealed that the GBX2 expression decreased as the BIO concentration increased (Kim et al., 2018).
  • To confirm whether the effect of BIO on midbrain specification was indeed through the activation of canonical Wnt signal, other small molecules that inhibit GSK3 were tested in different modes of action, such as 1- AKP and LiCl on human ESC-derived NPCs. LiCl treatment elicited similar gene expression patterns (decreased expression of GBX2) as BIO treatment, although the fold changes in gene expression were lower than those of the other inhibitors. These data support that midbrain-specific gene expression results from the activation of canonical Wnt signal via GSK3 inhibition (Kim et al., 2018).
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

Gbx2 begins to express in telencephalon approximately 14-18hpf (Wang et al., 2018).


 
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 for this KER is provided for zebrafish (Wang et al., 2018) and humans (Grassilli et al., 2014; Kim et al., 2018).

References

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

Grassilli, E. et al. (2014) ‘GSK3A is redundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis’, PLoS ONE, 9(7), pp. 1–8. doi: 10.1371/journal.pone.0100947.

Kim, J. Y. et al. (2018) ‘Wnt signal activation induces midbrain specification through direct binding of the beta-catenin/TCF4 complex to the EN1 promoter in human pluripotent stem cells’, Experimental & Molecular Medicine, 50, p. 24. doi: 10.1038/s12276-018-0044-y.

Wang, Z. et al. (2018) ‘The role of gastrulation brain homeobox 2 (gbx2) in the development of the ventral telencephalon in zebrafish embryos’, Differentiation, 99(December 2017), pp. 28–40. doi: 10.1016/j.diff.2017.12.005.