Laminin α5 is necessary for submandibular gland epithelial morphogenesis and influences FGFR expression through β1 integrin signaling

Laminin alpha chains have unique spatiotemporal expression patterns during development and defining their function is necessary to understand the regulation of epithelia] morphogenesis. We investigated the function of laminin alpha 5 in mouse submandibular glands (SMGs). Lama5(-/-) SMGs have a striking phenotype: epithelial clefting is delayed, although proliferation occurs; there is decreased FGFR1b and FGFR2b, but no difference in Lamal expression; later in development, epithelial cell organization and lumen formation are disrupted. In wild-type SMGs alpha 5 and oil are present in epithelial clefts but as branching begins a5 expression increases while alpha l decreases. Lama5 siRNA decreased branching, p42 MAPK phosphorylation, and FGFR expression, and branching was rescued by FGF10. FGFR siRNA decreased Lama5 suggesting that FGFR signaling provides positive feedback for Lama5 expression. Anti-beta 1 integrin antibodies decreased FGFR and Lama5 expression, suggesting that [ I integrin signaling provides positive feedback for Lama5 and FGFR expression. Interestingly, the 1tga3(-/-) :Itga6(-/-) SMGs have a similar phenotype to Lania5(-/-). Our findings suggest that laminin alpha 5 controls SMG epithelial morphogenesis through I integrin signaling by regulating FGFR expression, which also reciprocally regulates the expression of Lama5. These data link changes in basement membrane composition during branching morphogenesis with FGFR expression and signaling. (c) 2007 Elsevier Inc. All rights reserved.