IMPAIRED LUNG BRANCHING MORPHOGENESIS IN THE ABSENCE OF FUNCTIONAL EGF RECEPTOR

The mammalian lung develops through branching morphogenesis which is c ontrolled by growth factors, hormones, and extracellular matrix protei ns. We have evaluated the role of EGF-receptor signaling in lung morph ogenesis by analyzing the developmental phenotype of lungs in mice wit h an inactivated the EGF-receptor gene both in vivo and in organ cultu re. Neonatal EGF-receptor-deficient mice often show evidence of lung i mmaturity which can result in visible respiratory distress. The lungs of these mutant mice had impaired branching and deficient alveolizatio n and septation, resulting in a 50% reduction in alveolar volume and, thus, a markedly reduced surface for gas exchange, The EGF-receptor in activation also resulted in type II pneumocyte immaturity, which was a pparent from their increased glycogen content and a reduced number of lamellar bodies, The defective branching was already evident at Day 12 of embryonic development. When explants of embryonic lungs from Day 1 2 embryos were cultured under defined conditions, the branching defect in EGF-receptor-deficient lungs was even more pronounced, with only h alf as many terminal buds as normal lungs. EGF treatment stimulated th e expression of surfactant protein C and thyroid transcription factor- 1 in cultured normal lungs, but not in EGF-receptor deficient lungs, s uggesting that EGF-receptor signaling regulates the expression of thes e marker genes during type II pneumocyte maturation, Taken together, o ur data indicate that signal transduction through the EGF receptor pla ys a major role in lung development and that its inactivation leads to a respiratory distress like syndrome. (C) 1997 Academic Press.