The Hippo/Yap pathwayis a wll-conserved signaling cascade that regulates cell proliferation and dfferentiationto control organsize and stem/progenitor cell behavior.Following airway injury,Yap was dynamically regulate...The Hippo/Yap pathwayis a wll-conserved signaling cascade that regulates cell proliferation and dfferentiationto control organsize and stem/progenitor cell behavior.Following airway injury,Yap was dynamically regulated in regenerating airway epithelial clls.To deter.mine the role ofHippo signaling in the lung,the mammalian Hippo kinases,Mst1 and Mst2,were deleted in epithelial cells ofthe embry-onic 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 followving 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 prolif-eration and inhibited dfferentiation of human bronchial epithelial cells in vitro.Loss of Mst1/2 and expression ofYAP regulated transcrip-tional targets controlling cell proliferation and diferentiation,including Ajuba LIM protein.Ajuba was required forthe effects ofYAP oncell proliferation in vitro.Hippo/Yapsignaling regulates Ajuba and controls proliferation and diferentiation oflung epithelial progenitor cells.展开更多
基金This work was supported by National Heart,Lung,and Blood Institute and Lung Repair and Re generation Consortium(LRRC)U01-110964 to JA.W.and A-K.PLung Map U01-HL122642 to JA.W.,B.R.S..and A-K.P.
文摘The Hippo/Yap pathwayis a wll-conserved signaling cascade that regulates cell proliferation and dfferentiationto control organsize and stem/progenitor cell behavior.Following airway injury,Yap was dynamically regulated in regenerating airway epithelial clls.To deter.mine the role ofHippo signaling in the lung,the mammalian Hippo kinases,Mst1 and Mst2,were deleted in epithelial cells ofthe embry-onic 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 followving 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 prolif-eration and inhibited dfferentiation of human bronchial epithelial cells in vitro.Loss of Mst1/2 and expression ofYAP regulated transcrip-tional targets controlling cell proliferation and diferentiation,including Ajuba LIM protein.Ajuba was required forthe effects ofYAP oncell proliferation in vitro.Hippo/Yapsignaling regulates Ajuba and controls proliferation and diferentiation oflung epithelial progenitor cells.
