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Key Event Title
six1b expression, increased
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Repression of Gbx2 expression leads to increased mortality||KeyEvent||Vid Modic (send email)||Under development: Not open for comment. Do not cite|
Key Event Description
Six1b is predicted to have DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in several processes, including muscle organ development; nervous system development; and regulation of skeletal muscle cell proliferation. Human ortholog(s) of this gene implicated in autosomal dominant nonsyndromic deafness; branchiootorenal syndrome; and nephroblastoma. Orthologous to human SIX1 (SIX homeobox 1) (ZFIN Gene: Six1b, n.d.).
Six1b is a Member of the Pax–Six1b–Eya–Dach ( paired box–sine oculis homeobox–eyes absent– dachshund) gene regulatory network, involved in the development of numerous organs and tissues (Bessarab et al., 2004; Bricaud et al., 2006). It has been proposed to play an important role in inner ear development (Baker & Bronner-Fraser, 2001; Whitfield et al., 2002). Six1b expression appears to be regulated by pax2b and also by foxi1 (forkhead box I1) as expected for an early inducer of the otic placode (Bricaud et al., 2006).
Six1b promotes hair cell fate and, conversely, inhibits neuronal fate by differentially affecting cell proliferation and cell death in these lineages. Gain/loss-of-function experiment results indicate that, when six1 is overexpressed, not only are fewer neural progenitors formed but many of these progenitors do not go on to differentiate into neurons (Bricaud et al., 2006).
How It Is Measured or Detected
Inhibition of expression can be measured with reverse transcription polymerase chain reaction (RT-PCR). This technique is primarily used to measure the amount of specific RNA which is achieved by monitoring the amplification reaction using fluorescence, a technique called real-time PCR or quantitative PCR (qPCR) (Wong & Medrano, 2005). Combined RT-PCR and qPCR are routinely used for analysis of gene expression.
Domain of Applicability
Evidence was provided for vertebrates ((Brodbeck & Englert, 2004; Heanue et al., 1999; Li et al., 2003; Wawersik & Maas, 2000) and Drosophila (Bui et al., 2000).
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
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
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
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
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
Wong, M. L., & Medrano, J. F. (2005). Real-time PCR for mRNA quantitation. 39(1), 75–85. https://doi.org/10.2144/05391RV01
ZFIN Gene: six1b. (n.d.). Retrieved April 12, 2021, from https://zfin.org/ZDB-GENE-040426-230