A model system is described for defining the physiologic functions of mammalian cadherins in vivo. 129/Sv embryonic stem (ES) cells, stably transfected with a dominant negative N-cadherin mutant (NCADΔ) under the control of a promoter that only functions in postmitotic enterocytes during their rapid, orderly, and continuous migration up small intestinal villi, were introduced into normal C57B1/6 (B6) blastocysts. In adult B6 mutually implies 129/Sv chimeric mice, each villus receives the cellular output of several surrounding monoclonal crypts. A polyclonal villus located at the boundary of 129/Sv- and B6-derived intestinal epithelium contains vertical coherent bands of NCADΔ-producing enterocytes plus adjacent bands of normal B6-derived enterocytes. A comparison of the biological properties of these cell populations established that NCADΔ disrupts cell-cell and cell-matrix contacts, increases the rate of migration of enterocytes along the crypt- villus axis, results in a loss of their differentiated polarized phenotype, and produces precocious entry into a death program. These data indicate that enterocytic cadherins am critical cell survival factors that actively maintain intestinal epithelial function in vivo.