IN-VIVO ANALYSIS OF CADHERIN FUNCTION IN THE MOUSE INTESTINAL EPITHELIUM - ESSENTIAL ROLES IN ADHESION, MAINTENANCE OF DIFFERENTIATION, ANDREGULATION OF PROGRAMMED CELL-DEATH

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 (NCAD Delta) un der the control of a promoter that only functions in postmitotic enter ocytes during their rapid, orderly, and continuous migration up small intestinal villi, were introduced into normal C57B1/6 (B6) blastocysts . In adult B6 <----> 129/Sv chimeric mice, each villus receives the ce llular output of several surrounding monoclonal crypts. A polyclonal v illus located at the boundary of 129/Sv- and B6-derived intestinal epi thelium contains vertical coherent bands of NCAD Delta-producing enter ocytes plus adjacent bands of normal B6-derived enterocytes. A compari son of the biological properties of these cell populations established that NCAD Delta disrupts cell-cell and cell-matrix contacts, increase s the rate of migration of enterocytes along the crypt-villus axis, re sults in a loss of their differentiated polarized phenotype, and produ ces precocious entry into a death program. These data indicate that en terocytic cadherins are critical cell survival factors that actively m aintain intestinal epithelial function in vivo.