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Relationship: 2436

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

Repression of Gbx2 expression leads to foxi1 expression, increased

Upstream event

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

Repression of Gbx2 expression

Downstream event

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

foxi1 expression, increased

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	Moderate	Low	Cataia Ives (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	Not Specified

Life Stage Applicability

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

Term	Evidence
Larvae	Moderate

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

Repression of Gbx2 expression leads to increased expression of foxi1.

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 Map 2.0

ID	Experimental Design	Species	Upstream Observation	Downstream Observation	Citation (first author, year)	Notes

Evidence Map

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

Title	First Author	Biological Plausibility	Dose Concordance	Temporal Concordance	Incidence Concordance

Biological Plausibility

Dose Concordance Evidence

Temporal Concordance Evidence

Incidence Concordance Evidence

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

Failure to detect the expression alterations of the remaining genes with WISH is likely due to the non-quantitative nature of the WISH technique, which can only detect marked differences in expression levels. It is additionally possible that gbx2 induction affected broad and low-level expression that was undetectable by their conventional WISH technique. Still, the qPCR and WISH results together confirmed the reliability of the comprehensive microarray analysis (Nakayama et al., 2017).

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

(Wang et al., 2018) have shown that gbx2 is expressed in zebrafish (Danio rerio) embryos only after the late gastrula stage in the anterior hindbrain.

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 gastrulation brain homebox (Gbx) group of transcription factor genes, composed of two genes, gbx1 and gbx2, in vertebrates, is also present in invertebrates (Chiang et al., 1995), and can be regarded as widely conserved among animals (Wang et al., 2018). Gbx2 functions in a variety of developmental processes after midbrain-hindbrain boundary (MHB) establishment. (Burroughs-Garcia et al., 2011) data demonstrate that the role of gbx2 in anterior hindbrain development is functionally conserved between zebrafish and mice. This gene was shown to be required for neural crest (NC) formation in mice (B. Li et al., 2009; Roeseler et al., 2012). In Xenopus gbx2 is the earliest factor for specifying neural crest (NC) cells, and that gbx2 is directly regulated by NC inducing signaling pathways, such as Wnt/β-catenin signaling (Li et al., 2009).

Foxi I class genes have been described in zebrafish(Hans et al., 2004; Solomon et al., 2003), humans (Larsson et al., 1995; Pierrou et al., 1994), mouse (Hulander et al., 1998; Overdier et al., 1997), rat (Clevidence et al., 1993) and Xenopus (Lef et al., 1994, 1996). However, it is unclear whether zebrafish foxi1 is orthologous to any one of these genes. The Xenopus FoxI1c (Lef et al., 1996), FoxI1a and FoxI1b genes (Lef et al., 1994) share the highest degree of sequence conservation with the zebrafish gene. The expression pattern of the two Xenopus pseudoallelic variants FoxI1a/b does not suggest functional similarity to zebrafish foxi1. Of the three Xenopus FoxI genes, FoxI1c (XFD-10) is most similar to foxi1 in sequence. However, Xenopus FoxI1c was reported to be expressed in the neuroectoderm and somites but not in the otic placode, unlike the pattern for foxi1 reported in (Lef et al., 1996). (Pohl et al., 2002) report provides a more detailed description of Xenopus FoxI1c, which suggests that this gene is expressed in preplacodal tissue and the branchial arches, similar to observations for zebrafish foxi1. Thus, it appears probable that Xenopus FoxI1c represents the ortholog of zebrafish foxi1 (Solomon et al., 2003).