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First published online 16 February 2005
doi: 10.1242/dev.01700
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1 Institut Cochin, INSERM U567, CNRS UMR8104, Université Paris V, 24 rue
du Fb St-Jacques, 75014 Paris, France
2 UMR-S INSERM U490, 45 rue des St-Pères, 75006 Paris, France
3 INSERM U434, 27 rue Juliette Dodu, 75010 Paris, France
4 Institut Curie, UMR 144, 75005 Paris, France
* Author for correspondence (e-mail: perret{at}cochin.inserm.fr)
Accepted 14 January 2005
Loss of Apc appears to be one of the major events initiating colorectal cancer. However, the first events responsible for this initiation process are not well defined and the ways in which different epithelial cell types respond to Apc loss are unknown. We used a conditional gene-ablation approach in transgenic mice expressing tamoxifen-dependent Cre recombinase all along the crypt-villus axis to analyze the immediate effects of Apc loss in the small intestinal epithelium, both in the stem-cell compartment and in postmitotic epithelial cells. Within 4 days, Apc loss induced a dramatic enlargement of the crypt compartment associated with intense cell proliferation, apoptosis and impairment of cell migration. This result confirms the gatekeeper role of Apc in the intestinal epithelium in vivo. Although Apc deletion activated ß-catenin signaling in the villi, we observed neither proliferation nor morphological change in this compartment. This highlights the dramatic difference in the responses of immature and differentiated epithelial cells to aberrant ß-catenin signaling. These distinct biological responses were confirmed by molecular analyses, revealing that Myc and cyclin D1, two canonical ß-catenin target genes, were induced in distinct compartments. We also showed that Apc is a crucial determinant of cell fate in the murine intestinal epithelium. Apc loss perturbs differentiation along the enterocyte, goblet and enteroendocrine lineages, and promotes commitment to the Paneth cell lineage through ß-catenin/Tcf4-mediated transcriptional control of specific markers of Paneth cells, the cryptdin/defensin genes.
Key words: APC, ß-Catenin, Intestine, Paneth cells, Differentiation
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