DEPLETION OF EPITHELIAL STEM-CELL COMPARTMENTS IN THE SMALL-INTESTINEOF MICE LACKING TCF-4

Mutations of the genes encoding APC or beta-catenin in colon carcinoma induce the constitutive formation of nuclear beta-catenin/Tcf-4 compl exes, resulting in activated transcription of Tcf target genes(1,2). T o study the physiological role of Tcf-4 (which is encoded by the Tcf71 2 gene), we disrupted Tcf712 by homologous recombination. Tcf712(-/-) mice die shortly after birth. A single histopathological abnormality w as observed. An apparently normal transition of intestinal endoderm in to epithelium occurred at approximately embryonic day (E) 14.5. Howeve r, no proliferative compartments were maintained in the prospective cr ypt regions between the villi. As a consequence, the neonatal epitheli um was composed entirely of differentiated, non-dividing villus cells. We conclude that the genetic program controlled by Tcf-4 maintains th e crypt stem cells of the small intestine. The constitutive activity o f Tcf-4 in APC-deficient human epithelial cells may contribute to thei r malignant transformation by maintaining stem-cell characteristics.