Mouse Crumbs3 sustains epithelial tissue morphogenesis in vivo

Abstract

The human apical protein CRB3 (Crb3 in mouse) organizes epithelial cell polarity. Loss of CRB3 expression increases the tumorogenic potential of cultured epithelial cells and favors metastasis formation in nude mice. These data emphasize the need of in vivo models to study CRB3 functions. Here, we report the phenotypic analysis of a novel Crb3 knockout mouse model. Crb3-deficient newborn mice show improper clearance of airways, suffer from respiratory distress and display perinatal lethality. Crb3 is also essential to maintain apical membrane identity in kidney epithelial cells. Numerous kidney cysts accompany these polarity defects. Impaired differentiation of the apical membrane is also observed in a subset of cells of the intestinal epithelium. This results in improper remodeling of adhesive contacts in the developing intestinal epithelium, thereby leading to villus fusion. We also noted a strong increase in cytoplasmic β-catenin levels in intestinal epithelial cells. β-catenin is a mediator of the Wnt signaling pathway, which is overactivated in the majority of colon cancers. In addition to clarifying the physiologic roles of Crb3, our study highlights that further functional analysis of this protein is likely to provide insights into the etiology of diverse pathologies, including respiratory distress syndrome, polycystic kidney disease and cancer.