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J. Biol. Chem., Vol. 279, Issue 49, 50670-50675, December 3, 2004

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Global Inhibition of Lef1/Tcf-dependent Wnt Signaling at Its Nuclear End Point Abrogates Development in Transgenic Xenopus Embryos^*

Tom Deroo¶, Tinneke Denayer||, Frans Van Roy**, and Kris Vleminckx

From the Developmental Biology Unit and the ^**Molecular Cell Biology Unit, Department for Molecular Biomedical Research, Ghent University-Flanders Interuniversity Institute for Biotechnology, 9052 Ghent, Belgium

Analysis of canonical Wnt signaling during vertebrate development by means of knock-out or transgenic approaches is often hampered by functional redundancy as well as pathway bifurcations downstream of the manipulated components. We report the design of an optimized chimera capable of blocking transcriptional activation of Lef1/Tcf--catenin target genes, thus enabling intervention with the canonical Wnt pathway at its nuclear end point. This construct was made hormone-inducible, both functionally and transcriptionally, and was transgenically integrated in Xenopus embryos. Down-regulation of target genes was clearly observed upon treatment of these embryos with dexamethasone. In addition, exposure of variously aged transgenic embryos to dexamethasone caused complex phenotypes with many new but also several recognizable features stemming from inhibition of canonical Wnt signaling. At least in some tissues, a significant reduction in cell proliferation and an increase in programmed cell death appeared to underlie these phenotypes. Our inducible transgenic system can serve a broad range of experimental settings designed to unveil new functional aspects of Lef1/Tcf--catenin signaling during vertebrate embryogenesis.

Received for publication, August 5, 2004 , and in revised form, September 13, 2004.

^* This work was supported by grants from the Belgian Federation Against Cancer and the Interuniversitaire Attractiepolen. 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. S1 and S2.

Both authors contributed equally to this work.

^¶ A postdoctoral researcher at the Flanders Interuniversity Institute for Biotechnology.

^|| Holds a fellowship from the Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen.

A postdoctoral fellow with the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen. To whom correspondence should be addressed. Tel.: 32-9-33-13-720; Fax: 32-9-33-13-609; E-mail: Kris.Vleminckx{at}dmbr.ugent.be.

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				T. Denayer, M. Locker, C. Borday, T. Deroo, S. Janssens, A. Hecht, F. van Roy, M. Perron, and K. Vleminckx Canonical Wnt Signaling Controls Proliferation of Retinal Stem/Progenitor Cells in Postembryonic Xenopus Eyes Stem Cells, August 1, 2008; 26(8): 2063 - 2074. [Abstract] [Full Text] [PDF]