A CORRELATION BETWEEN EPITHELIAL PROLIFERATION RATES, BASEMENT-MEMBRANE COMPONENT LOCALIZATION PATTERNS, AND MORPHOGENETIC POTENTIAL IN THEEMBRYONIC MOUSE LUNG

Lung epithelial branching morphogenesis results from a repetitive seri es of cleft and bud formation, a process dependent upon a complex inte raction with the surrounding mesenchyme. The present study describes t hese cleft- and bud-forming regions as autonomous morphogenetic compar tments within the embryonic day 11.5 (E11.5) mouse lung and directly c orrelates their identity with differences in epithelial proliferation rates and the localization pattern of specific basement membrane compo nents. Lung buds were cultured in vitro, in two-dimensional planes, an d labeled with a series of 5-bromo-2'-deoxyuridine (BrdU) pulses. Coll ectively, epithelial cells within actively budding regions of the bron chiolar tree demonstrated an at least 2.5-fold greater proliferation r ate than those situated in the adjacent cleft-forming regions. Epithel ial proliferation rates showed an inverse relationship with the degree of immunoreactivity of nidogen, laminin-1, fibronectin, and collagen IV within the underlying basement membrane. Epithelial cells dissected free from mesenchyme demonstrated cell-cell contact-dependent prolife ration, thus revealing a hierarchy between mesenchymal signaling and d irect epithelial cell-cell communication during branch formation, Diss ection of the E11.5 bronchiolar tree into specific distalbud and inter bud regions and their ir? vitro culture demonstrated differences in th eir autonomous morphogenetic potential. Tissue dissected from the dist al tips of the lung continued to branch, whereas tissue dissected from immediately adjacent cleft regions seldom branched. Isolated distalbu d tissue also continued to correlate regional differences in epithelia l proliferation rates and immunolocalization patterns of nidogen, lami nin-1, fibronectin, and collagen IV with branch formation. These resul ts support the basement membrane remodeling hypothesis, thus connectin g nidogen, collagen type IV, fibronectin, and laminin-1 localization w ith the molecular processes directing epithelial proliferation and sup porting bud outgrowth and cleft formation/stabilization during lung mo rphogenesis.