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

Hum Mol Genet. 2010 Feb 1;19(3):506-16. doi: 10.1093/hmg/ddp520. Epub 2009 Nov 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Chromosomes, Human, Pair 22 / genetics*
  • Disease Models, Animal
  • Disorders of Sex Development* / embryology
  • Disorders of Sex Development* / genetics*
  • Disorders of Sex Development* / metabolism*
  • Female
  • Gene Expression Regulation, Developmental
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • SOXE Transcription Factors / genetics
  • SOXE Transcription Factors / metabolism*
  • Testis / embryology
  • Testis / metabolism


  • SOX10 protein, human
  • SOX9 Transcription Factor
  • SOXE Transcription Factors
  • Sox9 protein, mouse