Loss of alpha 3 beta 1 integrin function results in an altered differentiation program in the mouse submandibular gland

Mammalian submandibular gland (SMG) development leads to the establishment of highly organized secretory acinar and nonsecretory ductal epithelial cel ls. The ability of maturing salivary epithelial cells to attain their diffe rentiated state has been shown to depend, in part, on interactions between extracellular matrix (ECM) proteins and their integrin receptors. In a sear ch for key regulators of salivary cell lineage, we have studied alpha3 beta 1 integrin, a receptor for the basement membrane protein laminin, by charac terizing embryonic day 18 (E18) SMGs isolated from mice carrying a targeted mutation in the alpha3 integrin gene. Transmission electron microscopy stu dies showed that the mutant SMGs exhibited an aberrant differentiation phen otype with defects in the apical-basal polarity axis and in the basement me mbrane. Based on immunohistochemistry and Western blot analyses, the alpha3 beta1-deficient SMGs had altered expression and/or localization of several ECM and adhesive molecules, including laminin beta1, fibronectin, alpha5 i ntegrin, and E-cadherin, These changes correlated with alterations in the a ctivation state of Ras-extracellular signal-regulated kinase (ERK), as well as the expression and/or localization of Cdc42 and RhoA, two Rho GTPases t hat regulate the organization of the actin cytoskeleton. We conclude that a lpha3 beta1 is required for normal salivary cell differentiation and that i ts absence affects multiple components of adhesive complexes and their asso ciated signalling pathways. (C) 2001 Wiley-Liss, Inc.