TY - JOUR
T1 - Laminin α5 is necessary for submandibular gland epithelial morphogenesis and influences FGFR expression through β1 integrin signaling
AU - Rebustini, Ivan T.
AU - Patel, Vaishali N.
AU - Stewart, Julian S.
AU - Layvey, Ann
AU - Georges-Labouesse, Elisabeth
AU - Miner, Jeffrey H.
AU - Hoffman, Matthew P.
N1 - Funding Information:
The authors would like to thank Harry Grant and Melinda Larsen for critical reading of the manuscript. This work was supported by the Intramural Research Program of the National Institute for Dental and Craniofacial Research at the National Institutes of Health.
PY - 2007/8/1
Y1 - 2007/8/1
N2 - Laminin α 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 α5 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 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 that 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 SMG 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.
AB - Laminin α 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 α5 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 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 that 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 SMG 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.
KW - Branching morphogenesis
KW - Fibroblast growth factor receptors
KW - Integrins α3, α6, β1
KW - Laminin α5
KW - Salivary gland development
UR - http://www.scopus.com/inward/record.url?scp=34447649936&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2007.04.031
DO - 10.1016/j.ydbio.2007.04.031
M3 - Article
C2 - 17601529
AN - SCOPUS:34447649936
SN - 0012-1606
VL - 308
SP - 15
EP - 29
JO - Developmental Biology
JF - Developmental Biology
IS - 1
ER -