Hippo/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung
Hippo/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung
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DOI：
10.1093/jmcb/mju046
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发表时间：
2015-02-01
影响因子：
5.5
通讯作者：
Whitsett, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Lange, Alexander W.;Sridharan, Anusha;Whitsett, Jeffrey A.
Hippo/雅普通路是一种高度保守的信号级联，其调节细胞增殖和分化以控制器官大小和干/祖细胞行为。气道损伤后，雅普在再生气道上皮细胞中受到动态调节。为了确定Hippo信号传导在肺中的作用，在胚胎和成熟小鼠肺的上皮细胞中删除哺乳动物Hippo激酶Mst 1和Mst 2。mst 1/2缺失可促进胎肺细胞增殖，抑制肺囊形成和上皮细胞分化。胚胎Mst 1/2缺失后，正常围产期肺成熟过程中细胞增殖的转录抑制和分化的激活受到负调控。在成人肺中，从细支气管上皮细胞中去除Mst 1/2引起气道增生和分化改变。在Mst 1/2缺失后，抑制性雅普磷酸化减少，雅普核定位和转录靶点增加，与经典的Hippo/雅普信号传导一致。雅普对体外培养的人支气管上皮细胞有促进增殖和抑制分化的作用。Mst 1/2的缺失和雅普调节的转录靶点的表达控制细胞增殖和分化，包括Ajuba LIM蛋白。雅普对体外培养的细胞增殖的影响需要筋骨草的参与。Hippo/雅普信号调节筋骨草并控制肺上皮祖细胞的增殖和分化。
The Hippo/Yap pathway is a well-conserved signaling cascade that regulates cell proliferation and differentiation to control organ size and stem/progenitor cell behavior. Following airway injury, Yap was dynamically regulated in regenerating airway epithelial cells. To determine the role of Hippo signaling in the lung, the mammalian Hippo kinases, Mst1 and Mst2, were deleted in epithelial cells of the embryonic and mature mouse lung. Mst1/2 deletion in the fetal lung enhanced proliferation and inhibited sacculation and epithelial cell differentiation. The transcriptional inhibition of cell proliferation and activation of differentiation during normal perinatal lung maturation were inversely regulated following embryonic Mst1/2 deletion. Ablation of Mst1/2 from bronchiolar epithelial cells in the adult lung caused airway hyperplasia and altered differentiation. Inhibitory Yap phosphorylation was decreased and Yap nuclear localization and transcriptional targets were increased after Mst1/2 deletion, consistent with canonical Hippo/Yap signaling. YAP potentiated cell proliferation and inhibited differentiation of human bronchial epithelial cells in vitro. Loss of Mst1/2 and expression of YAP regulated transcriptional targets controlling cell proliferation and differentiation, including Ajuba LIM protein. Ajuba was required for the effects of YAP on cell proliferation in vitro. Hippo/Yap signaling regulates Ajuba and controls proliferation and differentiation of lung epithelial progenitor cells.