title: Jagged1 is the major regulator of Notch-dependent cell fate in proximal airways.
abstract: BACKGROUND
  The Notch signaling pathway plays complex roles in developing lungs, including regulation of proximodistal fates, airway cell specification and differentiation. However, the specific Notch-mediated signals involved in lung development remain unclear.
  
  
  RESULTS
  Here we report that Jagged1 is expressed in a subset of bronchial and bronchiolar epithelial cells, where it controls proximal airway cell fate and differentiation. In agreement with previous studies involving disruption of all Notch signaling, we found that deletion of Jagged1 in airway epithelium increased the number of ciliated cells at the expense of Clara cells, a phenotype associated with downregulation of Hes1. Deletion of Jagged1 also led to an increased number of pulmonary neuroendocrine cells (PNEC), suggesting that Jagged1/Notch signaling inhibits PNEC cell fate. As expected, Jagged1 deletion did not affect alveolar cell differentiation, although alveolar septation was impaired, likely an indirect effect of proximal airway defects. Finally, in the postnatal lung, Jagged1 deletion induced mucous metaplasia, accompanied by downregulation of Hes1 and Hes5.
  
  
  CONCLUSIONS
  Our results demonstrate that Jagged1-mediated Notch signaling regulates multiple cell fate decisions as well as differentiation in the respiratory system to coordinate lung development and to maintain a balance of airway cell types in adult life.
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Shubing
authors.initials: S
authors.lastname: Zhang
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Loch
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
authors.forename: Keli
authors.initials: K
authors.lastname: Xu
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D019070:Cell Lineage; D004847:Epithelial Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D000072100:Jagged-1 Protein; D008168:Lung / Q000196:embryology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D055099:Neuroendocrine Cells / Q000378:metabolism; D010641:Phenotype; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins