2 SEPARATE DOMAINS OF LAMININ PROMOTE LUNG ORGANOGENESIS BY DIFFERENTMECHANISMS OF ACTION

Laminin is a major component of basement membranes. We previously repo rted that the globular region of laminin B chain(s) and the cross regi on of the A chain play an active role in mouse lung branching morphoge nesis. In this study, basic morphogenic cell behaviors modulated by la minin were analyzed in order to elucidate how this glycoprotein promot es lung development. Cocultures of epithelial and mesenchymal cells fr om mouse fetal lungs were used to determine the effect of site-specifi c monoclonal antibodies to laminin (AL-1, AL-2, AL-3, AL-4, and AL-5) on epithelial and mesenchymal cell adhesion, proliferation, and organo typic rearrangement. We found that monoclonal antibody AL-1, directed against the cross region of the laminin A chain, inhibited epithelial and mesenchymal cell attachment and had a selective antiproliferative effect on epithelial cells. In contrast, monoclonal antibody AL-5, dir ected against the globular region of the B chain(s), blocked epithelia l cell polarity. Immunohistochemical studies on epithelial-mesenchymal cocultures exposed to monoclonal antibody AL-5 revealed the absence o f laminin deposition at the epithelial-mesenchymal interface, whereas type collagen IV was present at this site. These findings suggest that each of the two laminin domains involved in lung development promotes morphogenesis by a different mechanism of action. The cross-region of the A chain mediates cell adhesion and epithelial cell proliferation, whereas the globular region of the laminin B chain(s) is critical for the process of basement membrane assembly and cell polarization. The combined effect of both laminin domains on epithelial and mesenchymal cells and on the interaction between them seems to be essential for no rmal lung branching morphogenesis. (C) 1995 Academic Press, Inc.