Weinstein M, Xu X, Ohyama K, Deng C X
Laboratory of Biochemistry and Metabolism, National Institute of Diabetes, Digestive and Kidney Diseases, 10 Center Drive, National Institutes of Health, Bethesda, MD, USA.
Development. 1998 Sep;125(18):3615-23. doi: 10.1242/dev.125.18.3615.
Mammalian lungs begin as an outpocket of the foregut, and depend on multiple stages of branching morphogenesis and alveogenesis to reach their final form. An examination of fgf receptor gene expression indicated that all four receptors (fgfr-1 to fgfr-4) are expressed in postnatal lungs at varying levels. We show that mice homozygous for a targeted mutation of fgfr-4 exhibited no overt abnormalities in the lungs or any other organ. However, mice doubly homozygous for disruptions of the fgfr-3 and fgfr-4 genes display novel phenotypes not present in either single mutant, which include pronounced dwarfism and lung abnormalities. Lungs of fgfr-3(-/-)fgfr-4(-/- )animals, which are normal at birth, are completely blocked in alveogenesis and do not form secondary septae to delimit alveoli. Consequently, air spaces in the lung are expanded and no alveoli can be seen. The mutant lungs failed to downregulate postnatal elastin deposition despite their normal levels of surfactant expression and cell proliferation. These data revealed a cooperative function of FGFR-3 and FGFR-4 to promote the formation of alveoli during postnatal lung development.
哺乳动物的肺最初是前肠的一个囊袋，其最终形态的形成依赖于分支形态发生和肺泡发生的多个阶段。对成纤维细胞生长因子受体（FGF受体）基因表达的研究表明，所有四种受体（FGFR-1至FGFR-4）在出生后的肺中均有不同程度的表达。我们发现，FGFR-4基因靶向突变的纯合小鼠在肺或其他任何器官中均未表现出明显异常。然而，FGFR-3和FGFR-4基因双敲除的纯合小鼠表现出了单一突变体中未出现的新表型，包括明显的侏儒症和肺部异常。FGFR-3(-/-)FGFR-4(-/-)动物的肺在出生时是正常的，但在肺泡发生过程中完全受阻，无法形成次级隔膜来界定肺泡。因此，肺内的气腔扩大，看不到肺泡。尽管突变肺中表面活性剂表达和细胞增殖水平正常，但它们未能下调出生后弹性蛋白的沉积。这些数据揭示了FGFR-3和FGFR-4在出生后肺发育过程中促进肺泡形成的协同作用。
