J. Cell Biol., Volume 141, Number 3, May 4, 1998 765-777

Effects of Forced Expression of an NH₂-terminal Truncated -Catenin on Mouse Intestinal Epithelial Homeostasis

Melissa H. Wong,^* Bonnee Rubinfeld, and Jeffrey I. Gordon^*

^* Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110; and  Onyx Pharmaceuticals, Richmond, California 94806 

-Catenin functions as a downstream component of the Wnt/Wingless signal transduction pathway and as an effector of cell-cell adhesion through its association with cadherins. To explore the in vivo effects of -catenin on proliferation, cell fate specification, adhesion, and migration in a mammalian epithelium, a human NH₂-terminal truncation mutant (N89-catenin) was expressed in the 129/Sv embryonic stem cell-derived component of the small intestine of adult C57Bl/6-ROSA26 129/Sv chimeric mice. N89-Catenin was chosen because mutants of this type are more stable than the wild-type protein, and phenocopy activation of the Wnt/Wingless signaling pathway in Xenopus and Drosophila. N89-Catenin had several effects. Cell division was stimulated fourfold in undifferentiated cells located in the proliferative compartment of the intestine (crypts of Lieberkühn). The proliferative response was not associated with any discernible changes in cell fate specification but was accompanied by a three- to fourfold increase in crypt apoptosis. There was a marked augmentation of E-cadherin at the adherens junctions and basolateral surfaces of 129/Sv (N89-catenin) intestinal epithelial cells and an accompanying slowing of cellular migration along crypt-villus units. 1-2% of 129/Sv (N89-catenin) villi exhibited an abnormal branched architecture. Forced expression of N89-catenin expression did not perturb the level or intracellular distribution of the tumor suppressor adenomatous polyposis coli (APC). The ability of N89-catenin to interact with normal cellular pools of APC and/or augmented pools of E-cadherin may have helped prevent the 129/Sv gut epithelium from undergoing neoplastic transformation during the 10-mo period that animals were studied. Together, these in vivo studies emphasize the importance of -catenin in regulating normal adhesive and signaling functions within this epithelium.

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