title: Emergence of a Wave of Wnt Signaling that Regulates Lung Alveologenesis by Controlling Epithelial Self-Renewal and Differentiation.
abstract: Alveologenesis is the culmination of lung development and involves the correct temporal and spatial signals to generate the delicate gas exchange interface required for respiration. Using a Wnt-signaling reporter system, we demonstrate the emergence of a Wnt-responsive alveolar epithelial cell sublineage, which arises during alveologenesis, called the axin2+ alveolar type 2 cell, or AT2Axin2. The number of AT2Axin2cells increases substantially during late lung development, correlating with a wave of Wnt signaling during alveologenesis. Transcriptome analysis, in vivo clonal analysis, and ex vivo lung organoid assays reveal that AT2sAxin2promote enhanced AT2 cell growth during generation of the alveolus. Activating Wnt signaling results in the expansion of AT2s, whereas inhibition of Wnt signaling inhibits AT2 cell development and shunts alveolar epithelial development toward the alveolar type 1 cell lineage. These findings reveal a wave of Wnt-dependent AT2 expansion required for lung alveologenesis and maturation.
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Frank
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA 94117, USA.
authors.forename: Tien
authors.initials: T
authors.lastname: Peng
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jarod A
authors.initials: JA
authors.lastname: Zepp
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Melinda
authors.initials: M
authors.lastname: Snitow
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Tiffaney L
authors.initials: TL
authors.lastname: Vincent
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Penkala
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Cui
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Herriges
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Morley
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Min Min
authors.initials: MM
authors.lastname: Lu
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: emorrise@mail.med.upenn.edu.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D002999:Clone Cells; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D004848:Epithelium / Q000196:embryology; D017930:Genes, Reporter; D019426:Integrases / Q000378:metabolism; D008168:Lung / Q000196:embryology*; D051379:Mice; D008954:Models, Biological; D038081:Organogenesis / Q000235:genetics; D009940:Organoids; D011650:Pulmonary Alveoli / Q000166:cytology / Q000196:embryology*; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; C045073:Cre recombinase; D019426:Integrases
keywords: Wnt; alveolus; cell fate; lung