LAMININ ALPHA-1 CHAIN SYNTHESIS IN THE MOUSE DEVELOPING LUNG - REQUIREMENT FOR EPITHELIAL-MESENCHYMAL CONTACT AND POSSIBLE ROLE IN BRONCHIAL SMOOTH-MUSCLE DEVELOPMENT

Laminins, the main components of basement membranes, are heterotrimers consisting of alpha, beta, and gamma polypeptide chains linked togeth er by disulfide bonds. Laminins-1 and -2 are both composed of beta 1 a nd gamma 1 chains and differ from each other on their alpha chain, whi ch is alpha 1 and alpha 2 for laminin-1 and -2, respectively. The pres ent study shows that whereas laminins-1 and -2 are synthesized in the mouse developing lung and in epithelial-mesenchymal cocultures derived from it, epithelial and mesenchymal monocultures lose their ability t o synthesize the laminin alpha 1 chain. Synthesis of laminin al chain however returns upon re-establishment of epithelial-mesenchymal contac t. Cell-cell contact is critical, since laminin alpha 1 chain is not d etected in monocultures exposed to coculture-conditioned medium or in epithelial-mesenchymal cocultures in which heterotypic cell-cell conta ct is prevented by an interposing filter. Immunohistochemical studies on cocultures treated with brefeldin A, an inhibitor of protein secret ion, indicated both epithelial and mesenchymal cells synthesize lamini n alpha 1 chain upon heterotypic cell-cell contact. In a set of functi onal studies, embryonic lung explants were cultured in the presence of monoclonal antibodies to laminin alpha 1, alpha 2, and beta/gamma cha ins. Lung explants exposed to monoclonal antibodies to laminin alpha 1 chain exhibited alterations in peribronchial cell shape and decreased smooth muscle development, as indicated by low levels of smooth muscl e alpha actin and desmin. Taken together, our studies suggest that lam inin alpha 1 chain synthesis is regulated by epithelial-mesenchymal in teraction and may play a role in airway smooth muscle development.