title: Hippo-Foxa2 signaling pathway plays a role in peripheral lung maturation and surfactant homeostasis.
abstract: Respiratory distress syndrome (RDS), which is induced by insufficient production of surfactant, is the leading cause of mortality in preterm babies. Although several transcription factors are known to be involved in surfactant protein expression, the molecular mechanisms and signaling pathways upstream of these transcription factors have remained elusive. Here, using mammalian Hippo kinases (Mst1/2, mammalian sterile 20-like kinase 1/2) conditional knockout mice, we demonstrate that Mst1/2 kinases are critical for orchestration of transcription factors involved in surfactant protein homeostasis and prevention of RDS. Mice lacking Mst1/2 in the respiratory epithelium exhibited perinatal mortality with respiratory failure and their lungs contained fewer type I pneumocytes and more immature type II pneumocytes lacking microvilli, lamellar bodies, and surfactant protein expression, pointing to peripheral lung immaturity and RDS. In contrast to previous findings of YAP (Yes-associated protein)-mediated canonical Hippo signaling in the liver and intestine, loss of Mst1/2 kinases induced the defects in pneumocyte differentiation independently of YAP hyperactivity. We instead found that Mst1/2 kinases stabilized and phosphorylated the transcription factor Foxa2 (forkhead box A2), which regulates pneumocyte maturation and surfactant protein expression. Taken together, our results suggest that the mammalian Hippo kinases play crucial roles in surfactant homeostasis and coordination of peripheral lung differentiation through regulation of Foxa2 rather than of YAP.
authors.affiliation: Department of Biological Sciences, National Creative Research Initiatives Center, Biomedical Research Center, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Chaeuk
authors.initials: C
authors.lastname: Chung
authors.forename: Tackhoon
authors.initials: T
authors.lastname: Kim
authors.forename: Miju
authors.initials: M
authors.lastname: Kim
authors.forename: Minchul
authors.initials: M
authors.lastname: Kim
authors.forename: Hoogeun
authors.initials: H
authors.lastname: Song
authors.forename: Tae-Shin
authors.initials: TS
authors.lastname: Kim
authors.forename: Eunjeong
authors.initials: E
authors.lastname: Seo
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Hanbyul
authors.initials: H
authors.lastname: Kim
authors.forename: Sang Kyum
authors.initials: SK
authors.lastname: Kim
authors.forename: Geon
authors.initials: G
authors.lastname: Yoo
authors.forename: Da-Hye
authors.initials: DH
authors.lastname: Lee
authors.forename: Deog-Su
authors.initials: DS
authors.lastname: Hwang
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kinashi
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
mesh_terms: D056809:Alveolar Epithelial Cells / Q000166:cytology; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D003433:Crosses, Genetic; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism*; D000090683:Hippo Signaling Pathway; D006706:Homeostasis; D008168:Lung / Q000196:embryology / Q000254:growth & development; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D037661:Pulmonary Surfactant-Associated Proteins / Q000378:metabolism*; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D013997:Time Factors; D000099317:Hippo Kinases
chemical_list: D051542:Hepatocyte Nuclear Factor 3-beta; D017346:Protein Serine-Threonine Kinases; D037661:Pulmonary Surfactant-Associated Proteins; D000090742:Serine-Threonine Kinase 3; C496503:Foxa2 protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C490818:Stk3 protein, mouse
keywords: lung development; non-canonical Hippo pathway