Peters K, Werner S, Liao X, Wert S, Whitsett J, Williams L
Program of Excellence in Molecular Biology, University of California at San Francisco 94143-0130.
EMBO J. 1994 Jul 15;13(14):3296-301. doi: 10.1002/j.1460-2075.1994.tb06631.x.
Mouse lung development begins when two lung buds sprout from the epithelium of the embryonic gut. Patterning of the airways is then accomplished by the outgrowth and repetitive branching of the two lung buds, a process called branching morphogenesis. One of the four fibroblast growth factor (FGF) receptor genes, FGFR2, is expressed in the epithelium of a number of embryonic organs including the lung buds. To block the function of FGFR2 during branching morphogenesis of the lung without affecting its function in other embryonic tissues, the human surfactant protein C promoter was used to target expression of a dominant negative FGFR2 exclusively to lung bud epithelium in transgenic mice. Newborn mice expressing the transgene were completely normal except that instead of normally developed lungs they had two undifferentiated epithelial tubes that extended from the bifurcation of the trachea down to the diaphragm, a defect that resulted in perinatal death. Thus, the dominant negative FGF receptor completely blocked airway branching and epithelial differentiation, without prohibiting outgrowth, establishing a specific role for FGFs in branching morphogenesis of the mammalian lung.
小鼠肺发育始于胚胎肠道上皮长出两个肺芽。气道的模式形成随后通过两个肺芽的生长和反复分支来完成，这一过程称为分支形态发生。四个成纤维细胞生长因子（FGF）受体基因之一的FGFR2，在包括肺芽在内的许多胚胎器官的上皮中表达。为了在肺的分支形态发生过程中阻断FGFR2的功能而不影响其在其他胚胎组织中的功能，人类表面活性蛋白C启动子被用于在转基因小鼠中将显性负性FGFR2的表达特异性靶向到肺芽上皮。表达转基因的新生小鼠除了没有正常发育的肺，而是有两个从气管分叉向下延伸至横膈膜的未分化上皮管外，其他完全正常，这种缺陷导致围产期死亡。因此，显性负性FGF受体完全阻断了气道分支和上皮分化，而不阻止生长，从而确定了FGF在哺乳动物肺分支形态发生中的特定作用。
