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Research Article |
Institute of Human Genetics and Anthropology,5 University of Freiburg, D-79106 Freiburg, Germany
Institute of Physiological Chemistry I,6 Biocenter, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany
Institute of Human Genetics,7 International Centre for Life, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 3BZ, United Kingdom
Department of Pharmacology,8 Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
ABSTRACT
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.
developmental biology, gene regulation, ovary, Sertoli cells, testis
1 Supported by the Plan de Perfeccionamiento de Doctores de la Junta de Andalucia to F.B. and by grants from the Deutsche Forschungsgemeinschaft to C.E. (En 280/6–1) and G.S. (Sche 194/15–1+2).
2 Correspondence: Gerd Scherer, Institute of Human Genetics and Anthropology, Breisacherstr. 33, D-79106 Freiburg, Germany. FAX: 49 761 270 7041; gerd.scherer{at}uniklinik-freiburg.de
3 Current address: Prince Henry's Institute of Medical Research, Monash Medical Centre, 246 Clayton Rd., Melbourne, Victoria 3168, Australia.
4 Current address: Leibniz Institute for Age Research-Fritz Lipmann Institute e.V. (FLI), Beutenbergstr. 11, D-07745 Jena, Germany.
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