Homozygous Inactivation of Sox9 Causes Complete XY Sex Reversal in Mice

Institute of Human Genetics and Anthropology, University of Freiburg, D-79106 Freiburg, Germany.
Biology of Reproduction (Impact Factor: 3.32). 02/2006; 74(1):195-201. DOI: 10.1095/biolreprod.105.045930
Source: PubMed


In the presence of the Y-chromosomal gene Sry, the bipotential mouse gonads develop as testes rather than as ovaries. The autosomal gene Sox9, a likely and possibly direct Sry target, can induce testis development in the absence of Sry. Sox9 is thus sufficient but not necessarily essential for testis induction. Mutational inactivation of one allele of SOX9/Sox9 causes sex reversal in humans but not in mice. Because Sox9(-/-) embryos die around Embryonic Day 11.5 (E11.5) at the onset of testicular morphogenesis, differentiation of the mutant XY gonad can be analyzed only ex vivo in organ culture. We have therefore conditionally inactivated both Sox9 alleles in the gonadal anlagen using the CRE/loxP recombination system, whereby CRE recombinase is under control of the cytokeratin 19 promoter. Analysis of resulting Sox9(-/-) XY gonads up to E15.5 reveals immediate, complete sex reversal, as shown by expression of the early ovary-specific markers Wnt4 and Foxl2 and by lack of testis cord and Leydig cell formation. Sry expression in mutant XY gonads indicates that downregulation of Wnt4 and Foxl2 is dependent on Sox9 rather than on Sry. Our results provide in vivo proof that, in contrast to the situation in humans, complete XY sex reversal in mice requires inactivation of both Sox9 alleles and that Sox9 is essential for testogenesis in mice.

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    • "1991; Foster et al. 1994; Wagner et al. 1994; Huang et al. 1999; Vidal et al. 2001; Chaboissier et al. 2004; Barrionuevo et al. 2006). These observations support the concept that the cell types of the genital ridges must be equally capable of testis and ovary development. "
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    • "Interestingly, Sox9, one of the most important genes expressed during testis determination in mammals [65], was found to be highly expressed in the catfish testis, and as a male-biased gene. Previous studies about Sox9 in mice [66]–[69] and frogs [70], [71] indicated its critical role in testis differentiation and development. Sox9, together with Dmrt1, is one of the key SRY targets in mammalian testis development. "
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