Human Molecular Genetics

Activation of =A6=C2-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 G=A8=A6n=A8=A6tique du
D=A8=A6veloppement Normal et Pathologique, Universit=A8=A6 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-Kono=A8=A6-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: chabo... at (no spam) unice.fr

Received November 14, 2007; Accepted January 16, 2008

ABSTRACT
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 =A6=C2-catenin signaling pathway. =A6=C2-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 =A6=C2-catenin
activation determines the fate of the gonad, with Rspo1 acting as a
crucial regulator of canonical =A6=C2-catenin signaling required for female
development.