Effects of forced expression of an NH2-terminal truncated β-catenin on mouse intestinal epithelial homeostasis

Melissa H. Wong, Bonnee Rubinfeld, Jeffrey I. Gordon

    Research output: Contribution to journalArticle

    165 Scopus citations

    Abstract

    ̄-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 β-catenin on proliferation, cell fate specification, adhesion, and migration in a mammalian epithelium, a human NH2-terminal truncation mutant (Δ89β- catenin) was expressed in the 129/Sv embryonic stem cell-derived component of the small intestine of adult C57B1/6-ROSA26 mutually implies 129/Sv chimeric mice. ΔN89β-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. Δ89β-Catenin had several effects. Cell division was stimulated four-fold in undifferentiated cells located in the proliferative compartment of the intestine (crypts of Lieberkuhn). 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 (ΔN89β-catenin) intestinal epithelial cells and an accompanying slowing of cellular migration along crypt-villus units. 1-2% of 129/Sv (ΔN89β-catenin) villi exhibited an abnormal branched architecture. Forced expression of ΔN89β-catenin expression did not perturb the level or intracellular distribution of the tumor suppressor adenomatous polyposis coli (APC). The ability of ΔN89β-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 β-catenin in regulating normal adhesive and signaling functions within this epithelium.

    Original languageEnglish (US)
    Pages (from-to)765-777
    Number of pages13
    JournalJournal of Cell Biology
    Volume141
    Issue number3
    DOIs
    StatePublished - May 4 1998

    ASJC Scopus subject areas

    • Cell Biology

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