TARGETED EXPRESSION OF A DOMINANT-NEGATIVE FGF RECEPTOR BLOCKS BRANCHING MORPHOGENESIS AND EPITHELIAL DIFFERENTIATION OF THE MOUSE LUNG
TARGETED EXPRESSION OF A DOMINANT-NEGATIVE FGF RECEPTOR BLOCKS BRANCHING MORPHOGENESIS AND EPITHELIAL DIFFERENTIATION OF THE MOUSE LUNG
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DOI：
10.1002/j.1460-2075.1994.tb06631.x
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发表时间：
1994-07-15
期刊：
影响因子：
11.4
通讯作者：
WILLIAMS, L
中科院分区：
文献类型：
--
作者：
PETERS, K;WERNER, S;WILLIAMS, L
当两个肺芽从胚胎肠的上皮细胞中发芽时，小鼠的肺发育开始。然后，气道的模式化通过两个肺芽的生长和重复分支来完成，这一过程称为分支形态发生。四种成纤维细胞生长因子（FGF）受体基因之一FGFR 2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期间阻断FGFR 2的功能而不影响其在其他胚胎组织中的功能，使用人表面活性蛋白C启动子将显性阴性FGFR 2的表达专门靶向转基因小鼠的肺芽上皮。表达转基因的新生小鼠是完全正常的，只是它们没有正常发育的肺，而是有两个未分化的上皮管，从气管分叉延伸到横膈膜，这是导致围产期死亡的缺陷。因此，显性负性FGF受体完全阻断气道分支和上皮分化，而不抑制生长，从而确立FGF在哺乳动物肺的分支形态发生中的特定作用。
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.