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J. Biol. Chem., Vol. 279, Issue 7, 5725-5733, February 13, 2004

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Murine Frizzled-1 Behaves as an Antagonist of the Canonical Wnt/-Catenin Signaling^*

Sergio Roman-Roman, De-Li Shi, Véronique Stiot, Eric Haÿ, Béatrice Vayssière, Teresa Garcia, Roland Baron, and Georges Rawadi¶

From the ProSkelia Pharmaceuticals, 102 route de Noisy, 93230 Romainville and the Groupe de Biologie Experimentale, CNRS UMR 7622, 9 quai Saint-Bernard, 75005 Paris, France

Activation of the Wnt signaling cascade provides key signals during development and in disease. Wnt signals are transduced by seven-transmembrane Frizzleds (Fzs) and the single transmembrane low density lipoprotein receptor-related proteins 5 or 6. In the course of the analysis of genes regulated by bone morphogenetic protein 2 in mesenchymal cells we found a significant induction of murine Frizzled-1 (mFz1) gene expression. Unexpectedly overexpression of mFz1 dramatically repressed the induction of alkaline phosphatase mediated by either bone morphogenetic protein 2 or Wnt3a in these cells. Moreover mFz1 overexpression significantly repressed both -catenin translocation into the nucleus and T cell factor signaling mediated by Wnt3a. Importantly microinjection of mFz1 transcript in Xenopus embryo inhibited the ability of Wnt1 to induce the expression of the Wnt/-catenin target gene Siamois in animal cap assay and secondary axis formation in whole embryo. By using chimeric constructs in which N- and C-terminal segments of mFz1 were replaced by the corresponding parts of Xfz3 we demonstrated that the antagonistic activity resides in the cysteine-rich domain of the N-terminal part. The antagonist activity of mFz1 could be prevented by overexpression of G_q-(305-359), which specifically uncouples G_q-coupled receptors, suggesting that G_q signaling contributes to the inhibition of Wnt/-catenin pathway by mFz1. This is the first time that a Frizzled receptor has been reported to antagonize Wnt/-catenin.

Received for publication, August 20, 2003 , and in revised form, November 14, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 33-1-4991-6199; Fax: 33-1-4991-5257; E-mail: georges.rawadi{at}proskelia.com.

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