Department of Respiratory Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan; and.
Am J Respir Cell Mol Biol. 2020 Feb;62(2):256-266. doi: 10.1165/rcmb.2019-0218OC.
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 and conditional knockout mice. We generated lung epithelium-specific and 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 (Sonic hedgehog) expression and regulates the FGF (fibroblast growth factor)-SHH feedback loop, thereby contributing to normal bronchial morphogenesis. We also found that TGF-β (transforming growth factor-β) stimulation induced 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.
TAZ（含 PDZ 结合基序的转录共激活因子）和 YAP（Yes 相关蛋白）是 Hippo 通路的关键分子。最近的研究表明，这些分子在肺发育中是必不可少的；然而，涉及这些分子的精确信号级联以及它们在肺发育中的作用差异仍不清楚。我们旨在使用肺上皮细胞特异性和条件性敲除小鼠来研究 YAP 和 TAZ 的功能。我们生成了肺上皮细胞特异性和条件性敲除小鼠，并研究了 YAP 和 TAZ 在肺发育中的功能。在成年小鼠的肺上皮细胞中选择性敲除 TAZ 会导致肺泡异常化，类似于肺气肿；而 YAP 缺失会导致胚胎阶段支气管形态发生中断。我们报告称，TAZ 和 YAP 在肺中顺序表达，这可以解释它们的不同表型。此外，我们报告称 YAP 刺激 （Sonic hedgehog）表达并调节 FGF（成纤维细胞生长因子）-SHH 反馈环，从而有助于正常的支气管形态发生。我们还发现 TGF-β（转化生长因子-β）刺激诱导肺上皮细胞中 表达，TAZ 和 YAP 均是该新途径所必需的。我们的研究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。
