Overexpressing dominant-negative FGFR2-IIIb impedes lung branching morphogenesis in pigs
Overexpressing dominant-negative FGFR2-IIIb impedes lung branching morphogenesis in pigs
复制标题
过度表达显性失活 FGFR2-IIIb 阻碍猪肺分支形态发生
DOI：
10.1016/j.jgg.2018.02.002
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发表时间：
2018-03-20
影响因子：
5.9
通讯作者：
Dai, Yifan
中科院分区：
文献类型：
--
作者：
Chen, Qin;Fang, Bin;Dai, Yifan
利用小鼠模型进行的遗传学研究表明，成纤维细胞生长因子受体2 - IIIb（FGFR2 - IIIb）在肺发育和分化中起着至关重要的作用。为了评估FGFR2 - IIIb在猪肺发育中的作用，我们采用体细胞核移植（SCNT）技术来制备转基因猪胎儿，使其过表达由人肺表面活性蛋白C（SP - C）启动子驱动的显性负性人FGFR2 - IIIb的跨膜形式（dnFGFR2 - IIIb - Tm）和可溶性形式（dnFGFR2 - IIIb - HFc），该启动子在肺上皮细胞中特异性表达。分别从3头和2头受体母猪中收集到8个dnFGFR2 - IIIb - Tm转基因猪胎儿和12个dnFGFR2 - IIIb - HFc转基因猪胎儿。在两种形式的dnFGFR2 - IIIb转基因胎儿中，肺上皮细胞中FGFR2 - IIIb的抑制导致肺叶变小和肺泡形成迟缓。此外，dnFGFR2 - IIIb - HFc转基因胎儿在肺发育方面表现出更严重的恶化。我们的研究结果表明，上皮细胞中FGFR2 - IIIb信号通路的中断阻碍了猪肺的正常分支和肺泡形成，但其严重程度低于在转基因小鼠中观察到的结果。dnFGFR2 - IIIb转基因猪是研究囊胚互补以及肺发育和器官发生机制的良好模型。版权所有（C）2018，中国科学院遗传与发育生物学研究所，中国遗传学会。由爱思唯尔有限公司和科学出版社出版。保留所有权利。
Genetic studies with mouse models have shown that fibroblast growth factor receptor 2-IIIb (FGFR2-IIIb) plays crucial roles in lung development and differentiation. To evaluate the effect of FGFR2-IIIb in pig lung development, we employed somatic cell nuclear transfer (SCNT) technology to generate transgenic pig fetuses overexpressing the transmembrane (dnFGFR2-IIIb-Tm) and soluble (dnFGFR2-IIIb-HFc) forms of the dominant-negative human FGFR2-IIIb driven by the human surfactant protein C (SP-C) promoter, which was specifically expressed in lung epithelia. Eight dnFGFR2-IIIb-Tm transgenic and twelve dnFGFR2-IIIb-HFc transgenic pig fetuses were collected from three and two recipient sows, respectively. Repression of FGFR2-IIIb in lung epithelia resulted in smaller lobes and retardation of alveolarization in both forms of dnFGFR2-IIIb transgenic fetuses. Moreover, the dnFGFR2-IIIb-HFc transgenic ones showed more deterioration in lung development. Our results demonstrate that disruption of FGFR2-IIIb signaling in the epithelium impedes normal branching and alveolarization in pig lungs, which is less severe than the results observed in transgenic mice. The dnFGFR2-IIIb transgenic pig is a good model for the studies of blastocyst complementation as well as the mechanisms of lung development and organogenesis. Copyright (C) 2018, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.