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First published online 31 March 2004
doi: 10.1242/dev.01087
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1 INSERM U470, Centre de Biochimie, Parc Valrose, 06108 Nice Cedex 2,
France
2 Program in Developmental Biology, Baylor College of Medicine, Houston, TX
77030, USA
3 Department of Molecular Genetics, University of Texas, MD Anderson Cancer
Center, Houston, TX 77030, USA
4 Departments of Endocrinology and of Cell Biology, Utrecht University, 3584-CH
Utrecht, The Netherlands
5 Institute for Biochemistry, University of Erlangen, D-91054 Erlangen,
Germany
* Author for correspondence (e-mail: schedl{at}unice.fr)
Accepted 7 January 2004
Sex determination in mammals directs an initially bipotential gonad to differentiate into either a testis or an ovary. This decision is triggered by the expression of the sex-determining gene Sry, which leads to the activation of male-specific genes including the HMG-box containing gene Sox9. From transgenic studies in mice it is clear that Sox9 is sufficient to induce testis formation. However, there is no direct confirmation for an essential role for Sox9 in testis determination. The studies presented here are the first experimental proof for an essential role for Sox9 in mediating a switch from the ovarian pathway to the testicular pathway. Using conditional gene targeting, we show that homozygous deletion of Sox9 in XY gonads interferes with sex cord development and the activation of the male-specific markers Mis and P450scc, and leads to the expression of the female-specific markers Bmp2 and follistatin. Moreover, using a tissue specific knock-out approach, we show that Sox9 is involved in Sertoli cell differentiation, the activation of Mis and Sox8, and the inactivation of Sry. Finally, double knock-out analyses suggest that Sox8 reinforces Sox9 function in testis differentiation of mice.
Key words: Sex determination, Gonads, Conditional gene targeting, Mouse
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