title: Epithelial Notch signaling regulates lung alveolar morphogenesis and airway epithelial integrity.
abstract: Abnormal enlargement of the alveolar spaces is a hallmark of conditions such as chronic obstructive pulmonary disease and bronchopulmonary dysplasia. Notch signaling is crucial for differentiation and regeneration and repair of the airway epithelium. However, how Notch influences the alveolar compartment and integrates this process with airway development remains little understood. Here we report a prominent role of Notch signaling in the epithelial-mesenchymal interactions that lead to alveolar formation in the developing lung. We found that alveolar type II cells are major sites of Notch2 activation and show by Notch2-specific epithelial deletion (Notch2(cNull)) a unique contribution of this receptor to alveologenesis. Epithelial Notch2 was required for type II cell induction of the PDGF-A ligand and subsequent paracrine activation of PDGF receptor-α signaling in alveolar myofibroblast progenitors. Moreover, Notch2 was crucial in maintaining the integrity of the epithelial and smooth muscle layers of the distal conducting airways. Our data suggest that epithelial Notch signaling regulates multiple aspects of postnatal development in the distal lung and may represent a potential target for intervention in pulmonary diseases.
authors.affiliation: Department of Pediatrics, National Taiwan University Hospital, Taipei 100, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei 100, Taiwan; tsaopn@ntu.edu.tw mmorimoto@cdb.riken.jp.
authors.forename: Po-Nien
authors.initials: PN
authors.lastname: Tsao
authors.affiliation: Laboratory for Lung Development, RIKEN Center of Developmental Biology, Kobe 650-0047, Japan;
authors.forename: Chisa
authors.initials: C
authors.lastname: Matsuoka
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan;
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Wei
authors.affiliation: Department of Respiratory Medicine, Kyoto University Hospital, Kyoto 606-8507, Japan;
authors.forename: Atsuyasu
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Respiratory Medicine, Kyoto University Hospital, Kyoto 606-8507, Japan;
authors.forename: Susumu
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Respiratory Medicine, Kyoto University Hospital, Kyoto 606-8507, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Department of Pediatrics, National Taiwan University Hospital, Taipei 100, Taiwan;
authors.forename: Hung-Kuan
authors.initials: HK
authors.lastname: Chen
authors.affiliation: Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei 100, Taiwan; Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 10617, Taiwan;
authors.forename: Thai-Yen
authors.initials: TY
authors.lastname: Ling
authors.affiliation: Columbia Center for Human Development, Department of Medicine, Columbia University, New York, NY 10027.
authors.forename: Munemasa
authors.initials: M
authors.lastname: Mori
authors.affiliation: Columbia Center for Human Development, Department of Medicine, Columbia University, New York, NY 10027.
authors.forename: Wellington V
authors.initials: WV
authors.lastname: Cardoso
authors.affiliation: Laboratory for Lung Development, RIKEN Center of Developmental Biology, Kobe 650-0047, Japan; tsaopn@ntu.edu.tw mmorimoto@cdb.riken.jp.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism; D005647:Fucosyltransferases / Q000235:genetics; D008168:Lung / Q000033:anatomy & histology / Q000378:metabolism*; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000033:anatomy & histology / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000033:anatomy & histology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D005647:Fucosyltransferases; C539426:Pofut1 protein, mouse
keywords: Notch; alveolar myofibroblast; alveologenesis; bronchial smooth muscle; epithelial–mesenchymal interactions