Hyperproliferation and defects in epithelial polarity upon conditional ablation of alpha-catenin in skin

When surface epithelium was conditionally targeted for ablation of alpha -c atenin, hair follicle development was blocked and epidermal morphogenesis w as dramatically affected, with defects in adherens junction formation, inte rcellular adhesion, and epithelial polarity. Differentiation occurred, but epidermis displayed hyperproliferation, suprabasal mitoses, and multinuclea ted cells. In vitro, alpha -catenin null keratinocytes were poorly contact inhibited and grew rapidly. These differences were not dependent upon inter cellular adhesion and were in marked contrast to keratinocytes conditionall y null for another essential intercellular adhesion protein, desmoplakin (D P). KO keratinocytes exhibited sustained activation of the Ras-MAPK cascade due to aberrations in growth factor responses. Thus, remarkably, features of precancerous lesions often attributed to defects in cell cycle regulator y genes can be generated by compromising the function of alpha -catenin.