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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 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 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 Supporting this KER

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

Gbx2 exhibits DNA-binding transcription factor activity, RNA polymerase II-specific. Involved in cerebellum development; iridophore differentiation; and telencephalon regionalization. Predicted to localize to nucleus. Is expressed in several structures, including midbrain hindbrain boundary neural keel; midbrain hindbrain boundary neural rod; midbrain neural rod; nervous system; and presumptive rhombomere 1 (ZFIN Gene: Gbx2, n.d.). After MHB establishment, murine gbx2 expression continues in the anterior hindbrain, suggesting later developmental roles for this gene. Li et al. (2002) showed different requirements for gbx2 in cerebellum formation depending on the loci along the mediolateral axis (J. Y. H. Li et al., 2002). In zebrafish, gbx2 expression persists in the isthmus until at least the hatching stage (Kikuta et al., 2003), and the roles of gbx2 are conserved in the developing anterior hindbrain, including nV cranial motor neurons, in zebrafish and mice (Burroughs-Garcia et al., 2011).

A number of studies have shown that Gbx2 represses many developmental regulatory genes during MHB development including foxi1b (Nakamura, 2001; Rhinn & Brand, 2001; Simeone, 2000). Thus, Gbx2 may be a multifunctional transcriptional factor, although the mechanisms of the differential regulation of its activity during development are unknown (Nakayama et al., 2017). In (Nakayama et al., 2017) study Gbx2 has been shown to downregulate Foxi1 in zebrafish embryos.

Foxi1 exhibits DNA-binding transcription factor activity. Involved in several processes, including animal organ development; epidermal cell fate specification; and neuron development. Predicted to localize to nucleus. Is expressed in several structures, including ectoderm; epibranchial ganglion; head; neural crest; and neurogenic field (ZFIN Gene: Foxi1, n.d.).

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

Foxi1 is one of the downstream genes regulated by gbx2 transcription factor. Downregulation of gbx2 leads to increased foxi1 expression in zebrafish embryos.

  • (Nakayama et al., 2017) sought to comprehensively identify the target genes of zebrafish gbx2 at the end of gastrulation by microarray analysis. Eight genes that had been shown by the microarray data to be downregulated (Group C, otx1b, otx2, hoxb5b, msi2b, neurog1; Group D, pou5f3; Group F, her5, foxi1) were indeed immediately downregulated in hsp-gbx2+ embryos. Most of the genes that were identified as upregulated or downregulated in the microarray analysis were confirmed by qPCR analysis. WISH (whole mount in situ hybridization) further confirmed the alterations in expression for 6 out of the 12 genes examined (otx2, otx1b, her5, hesx1, klf2a, and pou5f3). 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).
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

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).

References

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

Burroughs-Garcia, J., Sittaramane, V., Chandrasekhar, A., & Waters, S. T. (2011). Evolutionarily conserved function of Gbx2 in anterior hindbrain development. Developmental Dynamics, 240(4), 828–838. https://doi.org/10.1002/dvdy.22589

Chiang, C., Young, K. E., & Beachy, P. A. (1995). Control of Drosophila tracheal branching by the novel homeodomain gene unplugged, a regulatory target for genes of the bithorax complex. Development, 121(11), 3901–3912.

Clevidence, D. E., Overdier, D. G., Taot, W., Qian, X., Pani, L., Lait, E., & Costa, R. H. (1993). Identification of nine tissue-specific transcription factors of the hepatocyte nuclear factor 3/forkhead DNA-binding-domain family (tissue-specific transcription factors/gene family/differentiation). In Proc. Natl. Acad. Sci. USA (Vol. 90).

Hans, S., Liu, D., & Westerfield, M. (2004). Pax8 and Pax2a function synergistically in otic specification, downstream of the Foxi1 and Dlx3b transcription factors. Development, 131(20), 5091–5102. https://doi.org/10.1242/dev.01346

Hulander, M., Wurst, W., Carlsson, P., & Enerbäck, S. (1998). The winged helix transcription factor FKh10 is required for normal development of the inner ear. Nature Genetics, 20(4), 374–376. https://doi.org/10.1038/3850

Kikuta, H., Kanai, M., Ito, Y., & Yamasu, K. (2003). gbx2 Homeobox Gene Is Required for the Maintenance of the Isthmic Region in the Zebrafish Embryonic Brain. Developmental Dynamics, 228(3), 433–450. https://doi.org/10.1002/dvdy.10409

Larsson, C., Hellqvist, M., Pierrou, S., White, I., Enerback, S. and, & Carlsson, P. (1995). Chromosomal Localization of Six Human Forkhead Genes, freac-1 (FKHL5), -3 (FKHL7), -4 (FKHL8), -5 (FKHL9), -6 (FKHL10), and -8 (FKHL12). Genomics, 30, 464–469.

Lef, J., Clement, J. H., Oschwald, R., Köster, M., & Knöchel, W. (1994). Spatial and temporal transcription patterns of the forkhead related XFD-2/XFD-2′ genes in Xenopus laevis embryos. Mechanisms of Development, 45(2), 117–126. https://doi.org/10.1016/0925-4773(94)90025-6

Lef, J., Dege, P., Scheucher, M., Forsbach-Birk, V., Clement, J. H., & Knöchel, W. (1996). A fork head related multigene family is transcribed in Xenopus laevis embryos. International Journal of Developmental Biology, 40(1), 245–253. https://doi.org/10.1387/ijdb.8735935

Li, B., Kuriyama, S., Moreno, M., & Mayor, R. (2009). The posteriorizing gene Gbx2 is a direct target of Wnt signalling and the earliest factor in neural crest induction. Development, 136(19), 3267–3278. https://doi.org/10.1242/dev.036954

Li, J. Y. H., Lao, Z., & Joyner, A. L. (2002). Changing requirements for Gbx2 in development of the cerebellum and maintenance of the Mid/hindbrain organizer. Neuron, 36(1), 31–43. https://doi.org/10.1016/S0896-6273(02)00935-2

Nakamura, H. (2001). Regionalization of the optic tectum: Combinations of gene expression that define the tectum. Trends in Neurosciences, 24(1), 32–39. https://doi.org/10.1016/S0166-2236(00)01676-3

Nakayama, Y., Inomata, C., Yuikawa, T., Tsuda, S., & Yamasu, K. (2017). Comprehensive analysis of target genes in zebrafish embryos reveals gbx2 involvement in neurogenesis. Developmental Biology, 430(1), 237–248. https://doi.org/10.1016/j.ydbio.2017.07.015

Overdier, D. G., Ye, H., Peterson, R. S., Clevidence, D. E., & Costa, R. H. (1997). The Winged Helix Transcriptional Activator HFH-3 Is Expressed in the Distal Tubules of Embryonic and Adult Mouse Kidney*. In THE JOURNAL OF BIOLOGICAL CHEMISTRY (Vol. 272, Issue 21). https://doi.org/10.1074/jbc.272.21.13725

Pierrou, S., Hellqvist, M., Samuelsson, L., Enerbäck, S., & Carlsson, P. (1994). Cloning and characterization of seven human forkhead proteins: Binding site specificity and DNA bending. EMBO Journal, 13(20), 5002–5012. https://doi.org/10.1002/j.1460-2075.1994.tb06827.x

Pohl, B. S., Knöchel, S., Dillinger, K., & Knöchel, W. (2002). Sequence and expression of FoxB2 (XFD-5) and FoxI1c (XFD-10) in Xenopus embryogenesis. Mechanisms of Development, 117(1–2), 283–287. https://doi.org/10.1016/S0925-4773(02)00184-3

Rhinn, M., & Brand, M. (2001). The midbrain-hindbrain boundary organizer. Current Opinion in Neurobiology, 11(1), 34–42. https://doi.org/10.1016/S0959-4388(00)00171-9

Roeseler, D. A., Sachdev, S., Buckley, D. M., Joshi, T., & Wu, D. K. (2012). Elongation Factor 1 alpha1 and Genes Associated with Usher Syndromes Are Downstream Targets of GBX2. PLoS ONE, 7(11), 47366. https://doi.org/10.1371/journal.pone.0047366

Simeone, A. (2000). Positioning the isthmic organizer - Where Otx2 and Gbx2 meet. Trends in Genetics, 16(6), 237–240. https://doi.org/10.1016/S0168-9525(00)02000-X

Solomon, K. S., Kudoh, T., Dawid, I. B., & Fritz, A. (2003). Zebrafish foxi1 mediates otic placode formation and jaw development. Development, 130(5), 929–940. https://doi.org/10.1242/dev.00308

Wang, Z., Nakayama, Y., Tsuda, S., & Yamasu, K. (2018). The role of gastrulation brain homeobox 2 (gbx2) in the development of the ventral telencephalon in zebrafish embryos. Differentiation, 99(December 2017), 28–40. https://doi.org/10.1016/j.diff.2017.12.005

ZFIN Gene: foxi1. (n.d.). Retrieved April 12, 2021, from https://zfin.org/ZDB-GENE-030505-1

ZFIN Gene: gbx2. (n.d.). Retrieved April 12, 2021, from https://zfin.org/ZDB-GENE-020509-2