API

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Relationship: 2439

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

eya1 expression, inhibited leads to Increase, Cell death

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
eya1 expression, inhibited
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increase, Cell death

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
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
Embryo 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

Zebrafish Eya1 has a role in regulating apoptosis within developing otic vesicle. In mammals Eya1 dephosphorylates histone variant H2AX and thereby affects DNA repair and cell survival (Cook et al., 2009).

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

Zebrafish eya1 has a role in development of the cristae, statoacoustic ganglia, and lateral line system. Primary consequence of loss of eya1 function in the zebrafish embryo is premature apoptosis in precursors to these structures. Apoptosis has also resulted from loss of eya gene function in Drosophila and mouse (Bonini et al., 1993; Xu et al., 1999), these findings may reflect a general mechanism of suppression of apoptosis by Eya proteins. Evidence also indicates a role of Eya protein in regulating genes controlling precursor cell proliferation and survival during mammalian organogenesis (Li et al., 2003).

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 Eya1 has a role in regulating apoptosis within developing otic vesicle. In mammals Eya1 dephosphorylates histone variant H2AX and thereby affects DNA repair and cell survival (Cook et al., 2009).

  • Increased levels of apoptosis occur in the migrating primordia of the posterior lateral line in dog (the zebrafish mutation dog-eared that is defective in formation of the inner ear and lateral line sensory systems) embryos and as well as in regions of the developing otocyst that are mainly fated to give rise to sensory cells of the cristae. Because of the large number of apoptotic cells observed within the otic vesicle of dog mutants, it has been proposed that eya1 could act as a suppressor of apoptosis (Kozlowski et al., 2005). Eya1 could be required to prevent apoptosis in the hair cell lineage, whereas it could have opposite actions in the neuronal lineage (Bricaud et al., 2006).
  • With loss of eya1 function in the eye primordium of Drosophila, the eye progenitor cells die by programmed cell death early in the differentiation process (Sahly et al., 1999).
  • Ectopic cell death in the developing otic vesicle is not restricted to prospective crista cells in the lateral wall. Acridine orange staining of dog embryos and wild-type siblings at several times during development revealed that cell death can occur throughout the dog otic vesicle. Ectopic cell death throughout the otic vesicle is the likely cause of the smaller otic vesicles observed in dog embryos during embryogenesis (Kozlowski et al., 2005).
  • By 55 hpf, the expression of crista-specific genes is severely reduced or absent in dog embryos and crista sensory hair cell bundles are absent at 72 hpf, suggesting that they have failed to differentiate (Whitfield et al., 2002).
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

Zebrafish morphological defects of the otic vesicle are first obvious at 48 hpf, some 38 h after the onset of eya1 expression in the preplacodal domain, and 24 h after increased apoptosis is observed. By 48 hpf, otic vesicles of the weakest dog phenotypic class are slightly smaller and more oblong in shape than wild-type siblings. As the phenotypic severity increases, dog otic vesicles are less round at the anterior end, developing an indented or folded appearance. By 72 hpf, dog otic vesicles are visibly smaller than those of wild-type siblings and distortion of the anterior end of the vesicle is more pronounced. At 96 hpf, otic vesicles of the severe phenotypic class are significantly smaller than wild- type siblings and have a narrow, cylindrical appearance (Kozlowski et al., 2005).

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 was provided for zebrafish (Kozlowski et al., 2005; Sahly et al., 1999), other vertebrates and Drosophila (Li et al., 2003; Zimmerman et al., 1997) and mammals (Li et al., 2003).

References

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

Bever, M. M., & Fekete, D. M. (1999). Ventromedial focus of cell death is absent during development of Xenopus and zebrafish inner ears. Journal of Neurocytology, 28(10–11), 781–793. https://doi.org/10.1023/a:1007005702187

Bonini, N. M., Leiserson, W. M., & Benzer, S. (1993). The eyes absent gene: Genetic control of cell survival and differentiation in the developing Drosophila eye. Cell, 72(3), 379–395. https://doi.org/10.1016/0092-8674(93)90115-7

Bricaud, O., Leslie, A. C., & Gonda, S. (2006). Development/Plasticity/Repair The Transcription Factor six1 Inhibits Neuronal and Promotes Hair Cell Fate in the Developing Zebrafish (Danio rerio) Inner Ear. Journal of Neuroscience, 26(41), 10438–10451. https://doi.org/10.1523/JNEUROSCI.1025-06.2006

Cook, P. J., Ju, B. G., Telese, F., Wang, X., Glass, C. K., & Rosenfeld, M. G. (2009). Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature, 458(7238), 591–596. https://doi.org/10.1038/nature07849

Kozlowski, D. J., Whitfield, T. T., Hukriede, N. A., Lam, W. K., & Weinberg, E. S. (2005). The zebrafish dog-eared mutation disrupts eya1, a gene required for cell survival and differentiation in the inner ear and lateral line. Developmental Biology, 277(1), 27–41. https://doi.org/10.1016/j.ydbio.2004.08.033

Li, X., Oghi, K. A., Zhang, J., Krones, A., Bush, K. T., Glass, C. K., Nigam, S. K., Aggarwal, A. K., Maas, R., Rose, D. W., & Rosenfeld, M. G. (2003). Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature, 426(6964), 247–254. https://doi.org/10.1038/nature02083

Rebay, I., Silver, S. J., & Tootle, T. L. (2005). New vision from Eyes absent: Transcription factors as enzymes. Trends in Genetics, 21(3), 163–171. https://doi.org/10.1016/j.tig.2005.01.005

Sahly, I., Andermann, P., & Petit, C. (1999). The zebrafish eya1 gene and its expression pattern during embryogenesis. Development Genes and Evolution, 209(7), 399–410. https://doi.org/10.1007/s004270050270

Tadjuidje, E., & Hegde, R. S. (2013). The Eyes Absent proteins in development and disease. Cellular and Molecular Life Sciences, 70(11), 1897–1913. https://doi.org/10.1007/s00018-012-1144-9

Whitfield, T. T., Riley, B. B., Chiang, M. Y., & Phillips, B. (2002). Development of the zebrafish inner ear. Developmental Dynamics, 223(4), 427–458. https://doi.org/10.1002/dvdy.10073

Xu, P. X., Adams, J., Peters, H., Brown, M. C., Heaney, S., & Maas, R. (1999). Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nature Genetics, 23(1), 113–117. https://doi.org/10.1038/12722

Zimmerman, J. E., Bui, Q. T., Kur Steingrimsson, E. [, Nagle, D. L., Fu, W., Genin, A., Spinner, N. B., Copeland, N. G., Jenkins, N. A., Bucan, M., & Bonini, N. M. (1997). Cloning and Characterization of Two Vertebrate Homologs of the Drosophila eyes absent Gene. Development, 124(23), 4819–4826.