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

Here, the authors investigate the function of laminin α5 in mouse submandibular glands (SMGs). They show that although laminin α5 is not required for gland initiation, it plays an important role in initial cleft formation and epithelial morphogenesis; it is necessary for sublingual gland formation, and later in development is required for epithelial cell organization and lumen formation. The data suggest that laminin α5 controls SMG epithelial morphogenesis through β1 integrin signaling by regulating FGFR expression, which also reciprocally regulates the expression of Lama5 and that this regulation is independent of Lama1. Lama5-/- SMGs have a striking phenotype: epithelial clefting is delayed, although proliferation occurs; there is decreased FGFR1b and FGFR2b, but no difference in Lama1 expression; later in development, epithelial cell organization and lumen formation are disrupted. In wild-type SMGs α5 and α1 are present in epithelial clefts but as branching begins α5 expression increases while α1 decreases. Lama5 siRNA decreased branching, p42 MAPK phosphorylation, and FGFR expression, and branching was rescued by FGF10. FGFR siRNA decreased Lama5 suggesting FGFR signaling provides positive feedback for Lama5 expression. Anti-β1 integrin antibodies decreased FGFR and Lama5 expression, suggesting that β1 integrin signaling provides positive feedback for Lama5 and FGFR expression. Interestingly, the Itga3-/-:Itga6-/- SMGs have a similar phenotype to Lama5-/-. Our findings suggest that laminin α5 controls mouse submandibular glands epithelial morphogenesis through β1 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.