Loss of alpha3beta1 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 cells. The ability of maturing salivary epithelial cells to attain their differentiated state has been shown to depend, in part, on interactions between extracellular matrix (ECM) proteins and their integrin receptors. In a search for key regulators of salivary cell lineage, we have studied alpha3beta1 integrin, a receptor for the basement membrane protein laminin, by characterizing embryonic day 18 (E18) SMGs isolated from mice carrying a targeted mutation in the alpha3 integrin gene. Transmission electron microscopy studies showed that the mutant SMGs exhibited an aberrant differentiation phenotype with defects in the apical-basal polarity axis and in the basement membrane. Based on immunohistochemistry and Western blot analyses, the alpha3beta1-deficient SMGs had altered expression and/or localization of several ECM and adhesive molecules, including laminin beta1, fibronectin, alpha5 integrin, and E-cadherin. These changes correlated with alterations in the activation state of Ras-extracellular signal-regulated kinase (ERK), as well as the expression and/or localization of Cdc42 and RhoA, two Rho GTPases that regulate the organization of the actin cytoskeleton. We conclude that alpha3beta1 is required for normal salivary cell differentiation and that its absence affects multiple components of adhesive complexes and their associated signalling pathways.
Menko
A S
AS
Department of Anatomy, Pathology and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. sue.menko@mail.tju.edu
Kreidberg
J A
JA
Ryan
T T
TT
Van Bockstaele
E
E
Kukuruzinska
M A
MA
D000199:Actins / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015153:Blotting, Western; D015820:Cadherins / Q000096:biosynthesis / Q000378:metabolism; D002448:Cell Adhesion; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D039201:Integrin alpha3beta1; D039482:Integrin alpha5; D016023:Integrins / Q000235:genetics* / Q000502:physiology*; D007633:Keratins / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D015398:Signal Transduction; D013363:Submandibular Gland / Q000196:embryology* / Q000648:ultrastructure; D013997:Time Factors; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D005353:Fibronectins; D039201:Integrin alpha3beta1; D039482:Integrin alpha5; D016023:Integrins; D007797:Laminin; D007633:Keratins; D020928:Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein