In vivo analysis of cadherin function in the mouse intestinal epithelium: essential roles in adhesion, maintenance of differentiation, and regulation 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) 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<->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 NCAD delta-producing enterocytes plus adjacent bands of normal B6-derived enterocytes. A comparison of the biological properties of these cell populations established that NCAD delta 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 are critical cell survival factors that actively maintain intestinal epithelial function in vivo.
Hermiston
M L
ML
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Gordon
J I
JI
D000199:Actins / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D015820:Cadherins / Q000032:analysis / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement; D002678:Chimera; D004847:Epithelial Cells; D004848:Epithelium / Q000737:chemistry; D007422:Intestines / Q000737:chemistry / Q000166:cytology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008871:Microvilli / Q000502:physiology; D008954:Models, Biological; D008969:Molecular Sequence Data; D017384:Sequence Deletion / Q000502:physiology
D000199:Actins; D015820:Cadherins