Forced expression of E-cadherin in the mouse intestinal epithelium slows cell migration and provides evidence for nonautonomous regulation of cell fate in a self-renewing system.
The adult mouse small intestinal epithelium is self-renewing. Its crypt-villus unit provides a model for studying many of the processes that occur during tissue morphogenesis such as control of proliferative status, specification of cell fate, regulation of differentiation, and induction of death. To assess the contributions of cell-cell and cell-substratum interactions to the coordinated control of these processes, 129/Sv embryonic stem (ES) cells, transfected with a recombinant DNA consisting of a fatty acid-binding protein gene (Fabp1) promoter that functions along the entire length of the crypt-villus axis linked to mouse E-cadherin, were introduced into normal C57Bl/6 (B6) blastocysts. Analyses of adult B6 <--> 129/Sv mice indicated that forced expression of E-cadherin suppresses proliferation and induces apoptosis in the crypt, and slows cell movement up the villus. The slowed migration is not accompanied by a change in distribution of terminal differentiation markers along the crypt-villus axis suggesting that differentiation is largely cell nonautonomous. To determine whether the slowed migration was a direct effect of forced expression of E-cadherin or a secondary effect of reduced crypt cell production, another Fabp promoter was used to restrict overproduction of E-cadherin to the villus epithelium of transgenic mice. Enterocytic migration was slowed, although proliferation and apoptosis were not perturbed in crypts. Augmentation of cellular E-cadherin pools was accompanied by an increase in beta-catenin levels. These findings establish that cadherins and their associated proteins modulate cellular migration, proliferation, and death programs in an adult vertebrate organ.
Hermiston
M L
ML
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Wong
M H
MH
Gordon
J I
JI
D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000502:physiology*; D002448:Cell Adhesion; D016923:Cell Death; D002454:Cell Differentiation; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000502:physiology; D019084:Fluorescent Antibody Technique, Indirect; D007413:Intestinal Mucosa / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008938:Mitosis; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D015820:Cadherins; C495272:Ctnna1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin