EFFECTS OF FORCED EXPRESSION OF AN NH2-TERMINAL TRUNCATED BETA-CATENIN ON MOUSE INTESTINAL EPITHELIAL HOMEOSTASIS

beta-Catenin functions as a downstream component of the Wnt/Wingless s ignal transduction pathway and as an effector of cell-cell adhesion th rough its association with cadherins. To explore the in vivo effects o f beta-catenin on proliferation, cell fate specification, adhesion, an d migration in a mammalian epithelium, a human NH2-terminal truncation mutant (Delta N89 beta-catenin) was expressed in the 129/Sv embryonic stem cell-derived component of the small intestine of adult C57Bl/6-R OSA26<->129/Sv chimeric mice. Delta N89 beta-Catenin was chosen becaus e 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. Delta N89 beta-Catenin had several effects. Cell divi sion was stimulated fourfold in undifferentiated cells located in the proliferative compartment of the intestine (crypts of Lieberkuhn). The proliferative response was not associated with any discernible change s in cell fate specification but was accompanied by a three-to fourfol d increase in crypt apoptosis. There was a marked augmentation of E-ca dherin at the adherens junctions and basolateral surfaces of 129/Sv (D elta N89 beta-catenin) intestinal epithelial cells and an accompanying slowing of cellular migration along crypt-villus units. 1-2% of 129/S v (Delta N89 beta-catenin) villi exhibited an abnormal branched archit ecture. Forced expression of Delta N89 beta-catenin expression did not perturb the level or intracellular distribution of the tumor suppress or adenomatous polyposis coli (APC). The ability of Delta N89 beta-cat enin to interact with normal cellular pools of APC and/or augmented po ols of E-cadherin may have helped prevent the 129/Sv gut epithelium fr om undergoing neoplastic transformation during the 10-mo period that a nimals were studied. Together, these in vivo studies emphasize the imp ortance of beta-catenin in regulating normal adhesive and signaling fu nctions within this epithelium.