Miettinen P J, Warburton D, Bu D, Zhao J S, Berger J E, Minoo P, Koivisto T, Allen L, Dobbs L, Werb Z, Derynck R
Department of Growth and Development, University of California at San Francisco, 94143, USA.
Dev Biol. 1997 Jun 15;186(2):224-36. doi: 10.1006/dbio.1997.8593.
The mammalian lung develops through branching morphogenesis which is controlled by growth factors, hormones, and extracellular matrix proteins. We have evaluated the role of EGF-receptor signaling in lung morphogenesis by analyzing the developmental phenotype of lungs in mice with an inactivated the EGF-receptor gene both in vivo and in organ culture. Neonatal EGF-receptor-deficient mice often show evidence of lung immaturity which can result in visible respiratory distress. The lungs of these mutant mice had impaired branching and deficient alveolization and septation, resulting in a 50% reduction in alveolar volume and, thus, a markedly reduced surface for gas exchange. The EGF-receptor inactivation also resulted in type II pneumocyte immaturity, which was apparent 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 12 embryos were cultured under defined conditions, the branching defect in EGF-receptor-deficient lungs was even more pronounced, with only half as many terminal buds as normal lungs. EGF treatment stimulated the expression of surfactant protein C and thyroid transcription factor-1 in cultured normal lungs, but not in EGF-receptor-deficient lungs, suggesting that EGF-receptor signaling regulates the expression of these marker genes during type II pneumocyte maturation. Taken together, our data indicate that signal transduction through the EGF receptor plays a major role in lung development and that its inactivation leads to a respiratory distress-like syndrome.
哺乳动物的肺通过分支形态发生进行发育，这一过程受生长因子、激素和细胞外基质蛋白的控制。我们通过在体内和器官培养中分析表皮生长因子（EGF）受体基因失活的小鼠肺的发育表型，评估了EGF受体信号在肺形态发生中的作用。新生的EGF受体缺陷小鼠常表现出肺不成熟的迹象，这可能导致明显的呼吸窘迫。这些突变小鼠的肺分支受损，肺泡化和间隔形成不足，导致肺泡体积减少50%，从而使气体交换表面显著减少。EGF受体失活还导致II型肺细胞不成熟，这从它们增加的糖原含量和减少的板层小体数量中明显可见。在胚胎发育第12天时，分支缺陷就已很明显。当将来自第12天胚胎的胚胎肺外植体在特定条件下培养时，EGF受体缺陷肺的分支缺陷更加明显，其终末芽数量只有正常肺的一半。EGF处理可刺激培养的正常肺中表面活性物质蛋白C和甲状腺转录因子-1的表达，但在EGF受体缺陷肺中则无此作用，这表明EGF受体信号在II型肺细胞成熟过程中调节这些标记基因的表达。综上所述，我们的数据表明，通过EGF受体的信号转导在肺发育中起主要作用，其失活会导致类似呼吸窘迫的综合征。
