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Human Molecular Genetics Advance Access originally published online on February 4, 2008
Human Molecular Genetics 2008 17(9):1264-1277; doi:10.1093/hmg/ddn016
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Activation of β-catenin signaling by Rspo1 controls differentiation of the mammalian ovary

Anne-Amandine Chassot1,2, Fariba Ranc1,2, Elodie P. Gregoire1,2, Hermien L. Roepers-Gajadien3,4, Makoto M. Taketo5, Giovanna Camerino6, Dirk G. de Rooij3, Andreas Schedl1,2 and Marie-Christine Chaboissier1,2,*

1 INSERM, U636, F-06108 Nice, France 2 Laboratoire de Génétique du Développement Normal et Pathologique, Université de Nice-Sophia Antipolis, F-06108 Nice, France 3 Department of Endocrinology, Utrecht University, 3584 CH Utrecht, The Netherlands 4 Center for Reproductive Medicine, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands 5 Department of Pharmacology, Graduate School of Medicine, Kyoto University Yoshida-Konoé-cho, Sakyo, Kyoto 606-8501, Japan 6 Dipartimento di Patologia Umana ed Ereditaria, Sezione di Biologia Generale e Genetica Medica, Universita di Pavia, Via Forlanini 14, 27100 Pavia, Italy

* To whom correspondence should be addressed. Tel: +33 492076451; Fax: +33 492076402; Email: chaboiss{at}unice.fr

Received November 14, 2007; Accepted January 16, 2008

The sex of an individual is determined by the fate of the gonad. While the expression of Sry and Sox9 is sufficient to induce male development, we here show that female differentiation requires activation of the canonical β-catenin signaling pathway. β-catenin activation is controlled by Rspo1 in XX gonads and Rspo1 knockout mice show masculinized gonads. Molecular analyses demonstrate an absence of female-specific activation of Wnt4 and as a consequence XY-like vascularization and steroidogenesis. Moreover, germ cells of XX knockout embryos show changes in cellular adhesions and a failure to enter XX specific meiosis. Sex cords develop around birth, when Sox9 becomes strongly activated. Thus, a balance between Sox9 and β-catenin activation determines the fate of the gonad, with Rspo1 acting as a crucial regulator of canonical β-catenin signaling required for female development.


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