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Molecular and Cellular Biology, November 2007, p. 7551-7559, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.01034-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Wnt/ß-Catenin Is Essential for Intestinal Homeostasis and Maintenance of Intestinal Stem Cells{triangledown} ,{dagger}

Tea Fevr,1 Sylvie Robine,2 Daniel Louvard,2 and Joerg Huelsken1*

Ecole Polytechnique Fédérale de Lausanne-ISREC (Swiss Institute for Experimental Cancer Research), Chemin des Boveresses 155, 1066 Epalinges, Switzerland,1 Morphogenesis and Intracellular Signalling, UMR 144, Institut Curie-CNRS, 26 rue d'Ulm, 75248 Paris Cedex 05, France2

Received 12 June 2007/ Returned for modification 19 July 2007/ Accepted 23 August 2007

The Wnt signaling pathway is deregulated in over 90% of human colorectal cancers. ß-Catenin, the central signal transducer of the Wnt pathway, can directly modulate gene expression by interacting with transcription factors of the TCF/LEF family. In the present study we investigate the role of Wnt signaling in the homeostasis of intestinal epithelium by using tissue-specific, inducible ß-catenin gene ablation in adult mice. Block of Wnt/ß-catenin signaling resulted in rapid loss of transient-amplifying cells and crypt structures. Importantly, intestinal stem cells were induced to terminally differentiate upon deletion of ß-catenin, resulting in a complete block of intestinal homeostasis and fatal loss of intestinal function. Transcriptional profiling of mutant crypt mRNA isolated by laser capture microdissection confirmed those observations and allowed us to identify genes potentially responsible for the functional preservation of intestinal stem cells. Our data demonstrate an essential requirement of Wnt/ß-catenin signaling for the maintenance of the intestinal epithelium in the adult organism. This challenges attempts to target aberrant Wnt signaling as a new therapeutic strategy to treat colorectal cancer.

* Corresponding author. Mailing address: Ecole Polytechnique Fédérale de Lausanne, ISREC (Swiss Institute for Experimental Cancer Research), Chemin des Boveresses 155, 1066 Epalinges, Switzerland. Phone: 41 21 692 5858. Fax: 41 21 652 6933. E-mail: joerg.huelsken{at}epfl.ch

{triangledown} Published ahead of print on 4 September 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2007, p. 7551-7559, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.01034-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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