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Int J Biochem Cell Biol. 2008;40(12):2889-900. doi: 10.1016/j.biocel.2008.06.006. Epub 2008 Jun 28.

Human SRY inhibits beta-catenin-mediated transcription.

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  • 1Prince Henry's Institute of Medical Research, Human Molecular Genetics Laboratory, Monash Medical Centre, Clayton, Australia.


In most mammals, sex is determined by the presence or absence of the SRY gene. SRY encodes a DNA-binding HMG-box transcription factor which, during embryogenesis, is the initial trigger of testis differentiation from the bipotential gonad, yet its precise mode of function remains unclear. In ovarian development, R-spondin1 and Wnt4 act through the Wnt/beta-catenin-signaling pathway to regulate TCF-dependent expression of unknown target genes and repress testis development. Conversely, SRY may be necessary to prevent the development of ovaries by inhibiting the action of ovarian-determining genes. We hypothesize that SRY prevents Wnt/beta-catenin signaling, thereby inhibiting ovarian development. In HEK293T cells, SRY repressed beta-catenin-mediated TCF-dependent gene activation in the presence of a specific GSK3beta inhibitor or an activated beta-catenin mutant, suggesting that SRY inhibits Wnt signaling at the level of beta-catenin. Three SRY mutant proteins with nuclear localization defects, encoded by XY male-to-female patients, failed to inhibit beta-catenin; surprisingly four SRY sex reversed mutants with defective DNA-binding activity showed near wild-type SRY inhibitory activity. Moreover the potent transactivator SRY-VP16 fusion protein also showed wild-type SRY inhibitory activity. Thus SRY inhibition of beta-catenin involves neither DNA-binding nor transactivation functions of SRY. beta-Catenin and SRY interact in vitro and SRY expression triggered beta-catenin localization into specific nuclear bodies in NT2/D1 and Hela cells. We conclude that SRY inhibits beta-catenin-mediated Wnt signaling by a novel nuclear function of SRY that could be important in sex determination.

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