title: Laminin alpha5 is necessary for submandibular gland epithelial morphogenesis and influences FGFR expression through beta1 integrin signaling.
abstract: Laminin alpha chains have unique spatiotemporal expression patterns during development and defining their function is necessary to understand the regulation of epithelial morphogenesis. We investigated the function of laminin alpha5 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 Lama1 expression; later in development, epithelial cell organization and lumen formation are disrupted. In wild-type SMGs alpha5 and alpha1 are present in epithelial clefts but as branching begins alpha5 expression increases while alpha1 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-beta1 integrin antibodies decreased FGFR and Lama5 expression, suggesting that beta1 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 alpha5 controls SMG epithelial morphogenesis through beta1 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.
authors.affiliation: Matrix and Morphogenesis Unit, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4370, USA.
authors.forename: Ivan T
authors.initials: IT
authors.lastname: Rebustini
authors.forename: Vaishali N
authors.initials: VN
authors.lastname: Patel
authors.forename: Julian S
authors.initials: JS
authors.lastname: Stewart
authors.forename: Ann
authors.initials: A
authors.lastname: Layvey
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Georges-Labouesse
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004848:Epithelium / Q000196:embryology; D005246:Feedback; D016220:Fibroblast Growth Factor 1 / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D039422:Integrin alpha3 / Q000235:genetics / Q000502:physiology; D039503:Integrin alpha6 / Q000235:genetics / Q000502:physiology; D019012:Integrin beta1 / Q000502:physiology*; D007797:Laminin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009024:Morphogenesis; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction; D013363:Submandibular Gland / Q000196:embryology* / Q000502:physiology
chemical_list: D039422:Integrin alpha3; D039503:Integrin alpha6; D019012:Integrin beta1; D007797:Laminin; D034741:RNA, Small Interfering; D017468:Receptors, Fibroblast Growth Factor; C097043:laminin alpha5; D016220:Fibroblast Growth Factor 1; C084098:laminin A; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2