title: Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors.
abstract: Basal cells are multipotent airway progenitors that generate distinct epithelial cell phenotypes crucial for homeostasis and repair of the conducting airways. Little is known about how these progenitor cells expand and transition to differentiation to form the pseudostratified airway epithelium in the developing and adult lung. Here, we show by genetic and pharmacological approaches that endogenous activation of Notch3 signaling selectively controls the pool of undifferentiated progenitors of upper airways available for differentiation. This mechanism depends on the availability of Jag1 and Jag2, and is key to generating a population of parabasal cells that later activates Notch1 and Notch2 for secretory-multiciliated cell fate selection. Disruption of this mechanism resulted in aberrant expansion of basal cells and altered pseudostratification. Analysis of human lungs showing similar abnormalities and decreased NOTCH3 expression in subjects with chronic obstructive pulmonary disease suggests an involvement of NOTCH3-dependent events in the pathogenesis of this condition.
authors.affiliation: Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Munemasa
authors.initials: M
authors.lastname: Mori
authors.affiliation: Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Mahoney
authors.affiliation: Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Stupnikov
authors.affiliation: Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Jesus R
authors.initials: JR
authors.lastname: Paez-Cortez
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Aleksander D
authors.initials: AD
authors.lastname: Szymaniak
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Xaralabos
authors.initials: X
authors.lastname: Varelas
authors.affiliation: Department of Developmental, Molecular, and Chemical Biology, School of Medicine, Tufts University, Boston, MA 02118, USA.
authors.forename: Dan B
authors.initials: DB
authors.lastname: Herrick
authors.affiliation: Department of Developmental, Molecular, and Chemical Biology, School of Medicine, Tufts University, Boston, MA 02118, USA.
authors.forename: James
authors.initials: J
authors.lastname: Schwob
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, NY 10032, USA Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA wvc2104@columbia.edu.
authors.forename: Wellington V
authors.initials: WV
authors.lastname: Cardoso
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008168:Lung / Q000196:embryology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D060888:Real-Time Polymerase Chain Reaction; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000196:embryology*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D013045:Species Specificity
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins
keywords: Airway differentiation; Basal cells; COPD; Jagged; Lung regeneration; Notch; Progenitor cells; p63