API

This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 2438

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

six1b expression, increased leads to eya1 expression, inhibited

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
six1b expression, increased
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
eya1 expression, inhibited

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 Low 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

Increase of six1b expression leads to inhibition of eya1.

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

Retinoic acid is required for both, expression of preplacodal ectoderm (PPE) markers Six1b and Eya1 and for the definition of their posterior boundary of expression (Schlosser, 2014). Six1b and Eya1 are not only expressed in otic placodes, but initially mark the whole preplacodal region (PPR) (Aghaallaei et al., 2007; Litsiou et al., 2005; Schlosser, 2006). Six1b expression appears to be regulated by pax2b and also by foxi1 ( forkheadbox I1) as expected for an early inducer ofthe otic placode (Bricaud et al., 2006). In the inner ear, six1b expression is restricted to the ventral otocyst in which the first hair cells differentiate and prospective SAG neurons delaminate. six1b promotes formation of hair cells by increasing cell proliferation and independently inhibits neuronal development by inducing apoptosis (Bessarab et al., 2004; Bricaud et al., 2006). In zebrafish, the eya1 gene is widely expressed in placode-derived sensory organs during embryogenesis but Eya1 function appears to be primarily required for survival of sensory hair cells in the developing ear and lateral line neuromasts (Kozlowski et al., 2005). Eya and Six together with the Dach protein directly interact to form a functional transcription factor. In this complex, the DNA binding function is provided by the Six protein, Eya mediates transcriptional activation and Dach proteins appear to function as cofactors (López-Ríos et al., 2003). A regulatory network of these proteins is thought to be active also during ear development (Whitfield et al., 2002) and vertebrate eye development (Wawersik & Maas, 2000).

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

Six1b is a transcription factor which inhibits expression of eya1.

  • RT-PCR analysis first detected six1b mRNA at mid-gastrula and its expression level increased at the beginning of segmentation, when in situ hybridization first detected regionalized expression. Shortly after the tail bud stage, weak expression was observed in the horseshoe-shaped domain surrounding the anterior neural plate, corresponding to position of the cranial placode. During the segmentation period, expression of six1 was observed in the olfactory placode and in the region that later give rise to the otic vesicle as well as anterior and posterior lateral line placodes. These elements of expression resemble the patterns reported for zebrafish eya1 (Bessarab et al., 2004; Sahly et al., 1999)
  • A regulatory network of DNA binding Six protein, eya1 transcriptional activator and Dach protein as cofactor is thought to be active during ear development (Whitfield et al., 2002) and vertebrate eye development (Wawersik & Maas, 2000).
  • Six1b gain-of-function experiment results showed that overexpression of six1b in zebrafish developing inner ear inhibited expression of eya1 (Bricaud et al., 2006).
  • Catalytically active phosphatase Eya1 in vertebrates cooperates with the DNA-binding protein Six1 to promote gene induction in response to sonic hedgehog (Shh) signaling and Eya1/Six1 together regulate Gli transcriptional activators (Eisner et al., 2015; 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
  • Interactions between Six1b and other members ofthe Pax–Six–Eya–Dach gene network, such as Eya1, also seem to differ between mouse and zebrafish. Zebrafish six1b inhibits eya1 expression, although its own expression is independent of the function of eya1. In mouse, Eya1 positively regulates Six1b expression (Xu et al., 1999), although its own expression is Six1b independent (Li et al., 2003; Zheng et al., 2003). Not only may interactions between six1b and eya1 differ in zebrafish relative to mouse but so might the interactions between six1b and the pax2 genes.
  • six1b function seems restricted to the otic ganglia even though it is expressed in other ganglia. However,we cannot rule out more subtle effects of six1b in other cranial ganglia, such as controlling the type of receptors or neurotransmitters expressed by these neurons. The neural crest contribution to other placodes (Baker & Bronner-Fraser, 2001) could also make six1b function less obvious than in the SAG.

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

Six1b acts early in both hair cell and neuronal lineages. The lack of suitable markers for hair cell or SAG neuronal precursors means that assaying the identity of the dividing cells before they actually differentiate is currently not possible. Latest time point for six1b loss or gain-of-function rescue seems to be 15-48 hpf (Bricaud et al., 2006) which coicides with the initial wave of hair cell and neurnoal differentiation between 24-48 hpf observed during inner ear development (Haddon & Lewis, 1996).

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

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

Key event relationship described herein has been mostly studied on zebrafish model (Bessarab et al., 2004; Bricaud et al., 2006). Evidence was also provided for Xenopus (Bever & Fekete, 1999; Kil & Collazo, 2001), Drosophila (Brodbeck & Englert, 2004; Heanue et al., 1999; Li et al., 2003), mouse (Brodbeck & Englert, 2004; Li et al., 2003)

References

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

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. https://doi.org/10.1016/j.ydbio.2007.04.022

Baker, C. V. H., & Bronner-Fraser, M. (2001). Vertebrate cranial placodes. I. Embryonic induction. Developmental Biology, 232(1), 1–61. https://doi.org/10.1006/dbio.2001.0156

Bessarab, D. A., Chong, S., & Korzh, V. (2004). Expression of Zebrafish six1 During Sensory Organ Development and Myogenesis. June, 781–786. https://doi.org/10.1002/dvdy.20093

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

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

Brodbeck, S., & Englert, C. (2004). Genetic determination of nephrogenesis: The Pax/Eya/Six gene network. Pediatric Nephrology, 19(3), 249–255. https://doi.org/10.1007/s00467-003-1374-z

Eisner, A., Pazyra-Murphy, M. F., Durresi, E., Zhou, P., Zhao, X., Chadwick, E. C., Xu, P. X., Hillman, R. T., Scott, M. P., Greenberg, M. E., & Segal, R. A. (2015). The Eya1 phosphatase promotes shh signaling during hindbrain development and oncogenesis. Developmental Cell, 33(1), 22–35. https://doi.org/10.1016/j.devcel.2015.01.033

Haddon, C., & Lewis, J. (1996). Early ear development in the embryo of the zebrafish, Danio rerio. Journal of Comparative Neurology, 365(1), 113–128. https://doi.org/10.1002/(SICI)1096-9861(19960129)365:1<113::AID-CNE9>3.0.CO;2-6

Heanue, T. A., Reshef, R., Davis, R. J., Mardon, G., Oliver, G., Tomarev, S., Lassar, A. B., & Tabin, C. J. (1999). Synergistic regulation of vertebrate muscle development by Dach2, Eya2, and Six1, homologs of genes required for Drosophila eye formation. www.genesdev.org

Kil, S. H., & Collazo, A. (2001). Origins of inner ear sensory organs revealed by fate map and time-lapse analyses. Developmental Biology, 233(2), 365–379. https://doi.org/10.1006/dbio.2001.0211

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

Lang, H., Bever, M. M., & Fekete, D. M. (2000). Cell Proliferation and Cell Death in the Developing Chick Inner Ear : The Journal of Comparative Neurology, 417(May 1999), 205–220.

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

Litsiou, A., Hanson, S., & Development, A. S. (2005). A balance of FGF, BMP and WNT signalling positions the future placode territory in the head. Development, 132(21), 4895. https://doi.org/10.1242/dev.01964

López-Ríos, J., Tessmar, K., Loosli, F., Wittbrodt, J., & Bovolenta, P. (2003). Six3 and Six6 activity is modulated by members of the groucho family. Development, 130, 185–195. https://doi.org/10.1242/dev.00185

Schlosser, G. (2006). Induction and specification of cranial placodes. Developmental Biology, 294(2), 303–351. https://doi.org/10.1016/j.ydbio.2006.03.009

Schlosser, G. (2014). Early embryonic specification of vertebrate cranial placodes. Wiley Interdisciplinary Reviews: Developmental Biology, 3(5), 349–363. https://doi.org/10.1002/wdev.142

Wawersik, S., & Maas, R. L. (2000). Vertebrate eye development as modeled in Drosophila. In Human Molecular Genetics (Vol. 9, Issue 6). http://hgu.mrc.ac.uk/Softdata/PAX6/

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

         Zheng, W., Huang, L., Wei, Z.-B., Silvius, D., Tang, B., & Pin-Xian, X. (2003). The role of Six1 in mammalian auditory system development. Development, 130, 3989–4000.                                                                https://doi.org/10.1242/dev.00628