Epithelial Expression of YAP and TAZ Is Sequentially Required in Lung Development
Epithelial Expression of YAP and TAZ Is Sequentially Required in Lung Development
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DOI：
10.1165/rcmb.2019-0218oc
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发表时间：
2020-02-01
影响因子：
6.4
通讯作者：
Nagase, Takahide
中科院分区：
文献类型：
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作者：
Isago, Hideaki;Mitani, Akihisa;Nagase, Takahide
TAZ(带有PDZ结合基序的转录共激活因子)和YAP(是相关蛋白)是河马途径的关键分子。最近的研究表明，这些分子在肺发育中是必不可少的；然而，涉及这些分子的确切信号级联以及它们在肺发育过程中的作用差异仍不清楚。我们的目标是使用肺上皮特异性TAZ和YAP条件性基因敲除小鼠来研究YAP和TAZ的功能。我们建立了肺上皮细胞特异性的TAZ和YAP条件性基因敲除小鼠，并研究了YAP和TAZ在肺发育中的作用。小鼠肺上皮细胞中选择性的TAZ缺乏症导致成人肺泡化异常，类似肺气肿，而YAP缺乏症在胚胎期引起支气管形态发生的破坏。我们报告了TAZ和YAP在肺中的顺序表达，这可以解释它们不同的表型。此外，我们发现YAP能刺激Sonic hedgehog(Sonic Hedgehog)的表达，调节成纤维细胞生长因子-SHH反馈环，从而促进正常的支气管形态发生。我们还发现，转化生长因子-β刺激诱导了肺上皮细胞Shh的表达，TAZ和YAP在这一新的途径中都是必不可少的。我们的结果为肺发育的分子机制提供了新的见解，并有助于更好地理解TAZ和YAP的特征。
TAZ (transcriptional coactivator with PDZ-binding motif) and YAP (Yes-associated protein) are key molecules of the Hippo pathway. Recent studies revealed that these molecules are essential in lung development; however, the precise signaling cascade involving these molecules and the differences in their roles during lung development remain unknown. We aimed to investigate YAP and TAZ functions using lung epithelium-specific Taz and Yap conditional knockout mice. We generated lung epithelium-specific Taz and Yap conditional knockout mice and investigated the functions of YAP and TAZ in lung development. Selective TAZ deficiency in mouse lung epithelial cells resulted in abnormal alveolarization, which mimics lung emphysema, in adults, whereas YAP deficiency caused disruption of bronchial morphogenesis during the embryonic stage. We report that TAZ and YAP are sequentially expressed in the lung and that this could explain their different phenotypes. Furthermore, we report that YAP stimulates Shh (Sonic hedgehog) expression and regulates the FGF (fibroblast growth factor)-SHH feedback loop, thereby contributing to normal bronchial morphogenesis. We also found that TGF-beta (transforming growth factor-beta) stimulation induced Shh expression in the lung epithelial cells, and both TAZ and YAP are essential in this novel pathway. Our results provide a novel insight into the molecular mechanisms underlying lung development and contribute to a better understanding of the characteristics of TAZ and YAP.