title: Notch signaling prevents mucous metaplasia in mouse conducting airways during postnatal development.
abstract: Goblet cell metaplasia and mucus overproduction contribute to the pathogenesis of chronic lung diseases, including asthma and chronic obstructive pulmonary disease (COPD). Notch signaling regulates cell fate decisions and is crucial in controlling goblet cell differentiation in the gut epithelium. Little is known, however, about how endogenous Notch signaling influences the goblet cell differentiation program that takes place in the postnatal lung. Using a combination of genetic and in vitro approaches here we provide evidence of a novel role for Notch in restricting goblet cell differentiation in the airway epithelium during the postnatal period. Conditional inactivation of the essential Notch pathway component Pofut1 (protein O-fucosyltransferase1) in Tgfb3-Cre-expressing mice resulted in an aberrant postnatal airway phenotype characterized by marked goblet cell metaplasia, decreased Clara cell number and increase in ciliated cells. The presence of the same phenotype in mice in which the Notch transcriptional effector Rbpjk was deleted indicated the involvement of the canonical Notch pathway. Lineage study in vivo suggested that goblet cells originated from a subpopulation of Clara cells largely present in proximal airways in which Notch was disrupted. The phenotype was confirmed by a panel of goblet cell markers, showed no changes in cell proliferation or altered expression of proinflammatory cytokines and was associated with significant downregulation of the bHLH transcriptional repressor Hes5. Luciferase reporter analysis suggested that Notch directly repressed MUC5AC transcription in lung epithelial cells. The data suggested that during postnatal life Notch is required to prevent Clara cells from differentiating into goblet cells.
authors.affiliation: Department of Pediatrics, National Taiwan University Hospital, Taipei 100, Taiwan. tsaopn@ntu.edu.tw
authors.forename: Po-Nien
authors.initials: PN
authors.lastname: Tsao
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Wei
authors.forename: Ming-Fang
authors.initials: MF
authors.lastname: Wu
authors.forename: Miao-Tzu
authors.initials: MT
authors.lastname: Huang
authors.forename: Hsien-Yi
authors.initials: HY
authors.lastname: Lin
authors.forename: Ming-Cheng
authors.initials: MC
authors.lastname: Lee
authors.forename: Kurt Ming-Chao
authors.initials: KM
authors.lastname: Lin
authors.forename: I-Jong
authors.initials: IJ
authors.lastname: Wang
authors.forename: Vesa
authors.initials: V
authors.lastname: Kaartinen
authors.forename: Liang-Tung
authors.initials: LT
authors.lastname: Yang
authors.forename: Wellington V
authors.initials: WV
authors.lastname: Cardoso
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D018450:Disease Progression; D005260:Female; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008679:Metaplasia / Q000378:metabolism; D051379:Mice; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D005647:Fucosyltransferases; D055271:Mucin 5AC; D051880:Receptors, Notch; D012097:Repressor Proteins; D053782:Transforming Growth Factor beta3; C489685:Hes5 protein, mouse; C524679:Muc5ac protein, mouse; C509045:Tgfb3 protein, mouse; C539426:Pofut1 protein, mouse