Hippo/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung

摘要

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, Mstl and Mst2, were deleted in epithelial cells of the embryonic and mature mouse lung. Mstl/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 duringnormal perinatal lung maturation were inversely regulated following embryonic Mstl j2 deletion. Ablation of Mstl/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 Mstl/2 deletion, consistent with canonical Hippo/Yap signaling. YAP potentiated cell proliferation and inhibited differentiation of human bronchial epithelial cells in vitro. Loss of Mstl/2 and expression of YAP regulated transcrip-tionaltargetscontrollingcell proliferation and differentiation, including Ajuba LIM protein. Ajuba was required fortheeffectsofYAPon cell proliferation in vitro. Hippo/Yap signaling regulates Ajuba and controls proliferation and differentiation of lungepithelial progenitor ceils.