title: Modulation of apical constriction by Wnt signaling is required for lung epithelial shape transition.
abstract: In lung development, the apically constricted columnar epithelium forms numerous buds during the pseudoglandular stage. Subsequently, these epithelial cells change shape into the flat or cuboidal pneumocytes that form the air sacs during the canalicular and saccular (canalicular-saccular) stages, yet the impact of cell shape on tissue morphogenesis remains unclear. Here, we show that the expression of Wnt components is decreased in the canalicular-saccular stages, and that genetically constitutive activation of Wnt signaling impairs air sac formation by inducing apical constriction in the epithelium as seen in the pseudoglandular stage. Organ culture models also demonstrate that Wnt signaling induces apical constriction through apical actomyosin cytoskeletal organization. Mathematical modeling reveals that apical constriction induces bud formation and that loss of apical constriction is required for the formation of an air sac-like structure. We identify MAP/microtubule affinity-regulating kinase 1 (Mark1) as a downstream molecule of Wnt signaling and show that it is required for apical cytoskeletal organization and bud formation. These results suggest that Wnt signaling is required for bud formation by inducing apical constriction during the pseudoglandular stage, whereas loss of Wnt signaling is necessary for air sac formation in the canalicular-saccular stages.
authors.affiliation: Departments of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Fumoto
authors.affiliation: Anatomy and Cell Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Takigawa-Imamura
authors.affiliation: Laboratory for Mouse Genetic Engineering, RIKEN Quantitative Biology Center, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Sumiyama
authors.affiliation: Departments of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kaneiwa
authors.affiliation: Departments of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita 565-0871, Japan akikuchi@molbiobc.med.osaka-u.ac.jp.
authors.forename: Akira
authors.identifier: 0000-0003-3378-9522
authors.initials: A
authors.lastname: Kikuchi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D016764:Cell Polarity / Q000502:physiology; D048430:Cell Shape; D003599:Cytoskeleton / Q000502:physiology; D004622:Embryo, Mammalian; D008168:Lung / Q000196:embryology*; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008962:Models, Theoretical; D009929:Organ Size; D038081:Organogenesis / Q000235:genetics; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000196:embryology*; D060449:Wnt Signaling Pathway / Q000502:physiology*
keywords: Apical constriction; Epithelium; Mark1; Mouse; Wnt