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Male development in mammals is normally initiated by the Y-linked gene  Sry , which activates expression of  Sox9 , leading to a cascade of gene activity required for testis formation. Although defects in this genetic cascade lead to human disorders of sex development (DSD), only a dozen DSD genes have been identified, and causes of 46,XX DSD (XX maleness) other than  SRY  translocation are almost completely unknown. Here, we show that transgenic expression of  Sox10 , a close relative of  Sox9 , in gonads of XX mice resulted in development of testes and male physiology. The degree of sex reversal correlated with levels of  Sox10  expression in different transgenic lines.  Sox10  was expressed at low levels in primordial gonads of both sexes during normal mouse development, becoming male-specific during testis differentiation. SOX10 protein was able to activate transcriptional targets of SOX9, explaining at a mechanistic level its ability to direct male development. Because over-expression of SOX10 alone is able to mimic the XX DSD phenotypes associated with duplication of human chromosome 22q13, and given that human SOX10 maps to 22q13.1, our results functionally implicate  SOX10  in the etiology of these DSDs.

Sox10 gain-of-function causes XX sex reversal in mice: implications for human 22q-linked disorders of sex development