Biotech China 2014

Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer

TypeWhite Paper Summary

The mammalian Y chromosome acts as a dominant male determinant as a result of the action of a single gene, Sry, whose role in sex determination is to initiate testis rather than ovary development from early bipotential gonads1, 2, 3. It does so by triggering the differentiation of Sertoli cells from supporting cell precursors, which would otherwise give follicle cells. The related autosomal gene Sox9 is also known from loss-of-function mutations in mice and humans to be essential for Sertoli cell differentiation4, 5; moreover, its abnormal expression in an XX gonad can lead to male development in the absence of Sry 6, 7. These genetic data, together with the finding that Sox9 is upregulated in Sertoli cell precursors just after SRY expression begins8, 9, has led to the proposal that Sox9 could be directly regulated by SRY. However, the mechanism by which SRY action might affect Sox9 expression was not understood. Here we show that SRY binds to multiple elements within a Sox9 gonad-specific enhancer in mice, and that it does so along with steroidogenic factor 1 (SF1, encoded by the gene Nr5a1 (Sf1)), an orphan nuclear receptor. Mutation, co-transfection and sex-reversal studies all point to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate Sox9 and then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. Our results open up the field, permitting further characterization of the molecular mechanisms regulating sex determination and how they have evolved, as well as how they fail in cases of sex reversal

Keywords
Authors
Name:Michael S. Wolfe
Name:J Liu
Name:Y Smith
Name:Ryohei Sekido
Name:Robin Lovell-Badge
Name:F Hunte
Name:Peter R Schreiner
Name:Stephen H Richardson
Name:Jun Xian Shen
Name:Ido Erev
Name:Arnon Lotem
Name:Thomas L Kukar
Name:Todd E Golde
Name:Anthony W. S Anthony W. S. Chan
Organizations
Organization:University of California

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