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Relationship: 2467


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

Increase, Cell death leads to Altered, inner ear development

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 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 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

Increased cell death in otic vesicle leads to abnormal inner ear development.

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

The vertebrate inner ear develops from the otic placode, an ectodermal thickening that appears early in development and invaginates to form the otic vesicle (Aghaallaei et al., 2007). Eya1 gene was shown to regulate cell death during development of otic vesicle (Abdelhak et al., 1997; Kozlowski et al., 2005; Schlosser, 2014; Whitfield et al., 2002; Zhou et al., 2017). Increased cell death resulted in smaller otic vesicle (Kozlowski et al., 2005).

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

Increased cell death in otic vesicle leads to sensory defects via malformations of inner ear and lateral line sensory systems (Kozlowski et al., 2005).

  • 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. 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).
  • After Six1 or Eya1 loss of function, the numbers of sensory receptors and neurons in the sense organs and ganglia derived from the olfactory, otic, lateral line, profundal/trigeminal, and epibranchial placodes are reduced, and only small, malformed sense organs develop that are abnormally patterned and functionally deficient (Schlosser, 2014).
  • Other cell types of the inner ear, including supporting cells and endolymph-producing cells, are also derived from the otic placode as are the sensory neurons of the vestibulocochlear ganglion, which innervate the hair cells. The lateral line placodes of fishes and amphibians also give rise to hair cells and supporting cells, which form small mechanosensory organs (neuromasts) distributed in lines along the body surface and involved in the detection of water movements. They also produce the sensory neurons innervating these receptor organs (Schlosser, 2014; Whitfield, 2002).
  • Dog-eared zebrafish mutants exibit increased death in otic vesicle during development; loss of cristae; abnormal macuae and semicircular canal system (Kozlowski et al., 2005; Whitfield et al., 1996, 2002). Dog-eared mutants are zebrafish model for human branchio-oto renal syndrome (Whitfield, 2002).
  • BOR (branchio-oto-renal) syndrome in humans is characterized by branchial cleft abnormalities, otic developmental defects and renal malformations. To date, autosomal dominant mutations in the EYA1 (Eyes Absent 1) gene are the most common genetic cause of BOR. EYA1 is the human homologue of the Drosophila gene eya (eyes absent), in which null mutations result in eyeless fly embryos due to apoptotic loss of eye disc cells (Bonini et al., 1993). Subsequent studies reported homologues of the eya gene in vertebrates (Duncan et al., 1997; Li et al., 2010).
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.

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 (Whitfield et al., 1996; Kozlowski et al., 2005), other vertebrates (Schlosser et al., 2008), mice (Johnson et al., 1999; Xu et al., 1999) and human (Bonini, Leiserson and Benzer, 1993).


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

Abdelhak, S., Kalatzis, V., Heilig, R., Compain, S., Samoson, D., Vincent, C., Weil, D., Cruaud, C., Sahly, I., Leibovici, M., Bitner-Glindzicz, M., & Francis, M. (1997). A human homologue of the Drosophila eyes absent gene underlies branchio-oto-renal (BOR) syndrome and identifies a novel gene family. Nature Genetics, 15, 157–167.

Aghaallaei, N., Bajoghli, B., & Czerny, T. (2007). Distinct roles of Fgf8, Foxi1, Dlx3b and Pax8/2 during otic vesicle induction and maintenance in medaka. Developmental Biology, 307(2), 408–420.

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.

Duncan, M. K., Kos, L., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., & Tomarev, S. I. (1997). Eyes absent: a gene family found in several metazoan phyla. In Mammalian Genome (Vol. 8). Spfinger-VerlagNew York Inc.

Johnson, K. R., Cook, S. A., Erway, L. C., Matthews, A. N., Sanford, L. P., Paradies, N. E., & Friedman, R. A. (1999). Inner ear and kidney anomalies caused by IAP insertion in an intron of the Eya1 gene in a mouse model of BOR syndrome. In Human Molecular Genetics (Vol. 8, Issue 4).

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.

Li, Y., Manaligod, J. M., & Weeks, D. L. (2010). EYA1 mutations associated with the branchio-oto-renal syndrome result in defective otic development in Xenopus laevis. Biol. Cell, 102, 277–292.

Schlosser, G. (2014). Early embryonic specification of vertebrate cranial placodes. Wiley Interdisciplinary Reviews: Developmental Biology, 3(5), 349–363.

Schlosser, G., Awtry, T., Brugmann, S. A., Jensen, E. D., Neilson, K., Ruan, G., Stammler, A., Voelker, D., Yan, B., Zhang, C., Klymkowsky, M. W., & Moody, S. A. (2008). Eya1 and Six1 promote neurogenesis in the cranial placodes in a SoxB1-dependent fashion. Developmental Biology, 320(1), 199–214.

Whitfield, T. T. (2002). Zebrafish as a Model for Hearing and Deafness. J Neurobiol, 53, 157–171.

Whitfield, T. T., Granato, M., Van Eeden, F. J. M., Schach, U., Brand, M., Furutani-Seiki, M., Haffter, P., Hammerschmidt, M., Heisenberg, C. P., Jiang, Y. J., Kane, D. A., Kelsh, R. N., Mullins, M. C., Odenthal, J., & Nüsslein-Volhard, C. (1996). Mutations affecting development of the zebrafish inner ear and lateral line. Development, 123, 241–254.

Whitfield, T. T., Riley, B. B., Chiang, M. Y., & Phillips, B. (2002). Development of the zebrafish inner ear. Developmental Dynamics, 223(4), 427–458.

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.

Zhou, J. J., Huang, Y., Zhang, X., Cheng, Y., Tang, L., & Ma, X. (2017). Eyes absent gene (EYA1) is a pathogenic driver and a therapeutic target for melanoma (Vol. 8, Issue 62).