1Department of Human Genetics; 2Department of Molecular Cell Biology, Leiden University Medical Center, Leiden; 3Department of Immunology, Utrecht University Medical Center, Utrecht, The Netherlands; 4Dept. Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, USA; 5Sheffi eld Kidney Institute, Sheffi eld University, Sheffi eld, United Kingdom; 6Department of Pediatrics and Pediatric Research Institute, Saint Louis University, St. Louis, USA

Mutations of the genes encoding APC or ß-catenin in colon carcinoma induce the constitutive formation of nuclear ß-catenin/Tcf-4 complexes, resulting in activated transcription of Tcf target genes1,2. To study the physiological role of Tcf-4 (which is encoded by the Tcf7l2 gene), we disrupted Tcf7l2 by homologous recombination. Tcf7l2-/- mice die shortly after birth. A single histopathological abnormality was observed. An apparently normal transition of intestinal endoderm into epithelium occurred at approximately embryonic day (E) 14.5. However, no proliferative compartments were maintained in the prospective crypt regions between the villi. As a consequence, the neonatal epithelium was composed entirely of differentiated, non-dividing villus cells. We conclude that the genetic program controlled by Tcf-4 maintains the crypt stem cells of the small intestine. The constitutive activity of Tcf-4 in APC-deficient human epithelial cells may contribute to their malignant transformation by maintaining stem-cell characteristics.