title: Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis.
abstract: Distal lung development occurs through coordinated induction of myofibroblasts, epithelial cells, and capillaries. Lunatic Fringe (Lfng) is a beta(1-3) N-acetylglucosamine transferase that modifies Notch receptors to facilitate their activation by Delta-like (Dll1/4) ligands. Lfng is expressed in the distal lung during saccular development, and deletion of this gene impairs myofibroblast differentiation and alveogenesis in this context. A similar defect was observed in Notch2(beta-geo/+)Notch3(beta-geo/beta-geo) compound mutant mice but not in Notch2(beta-geo/+) or Notch3(beta-geo/beta-geo) single mutants. Finally, to directly test for the role of Notch signaling in myofibroblast differentiation in vivo, we used ROSA26-rtTA(/+);tetO-CRE(/+);RBPJkappa(flox/flox) inducible mutant mice to show that disruption of canonical Notch signaling during late embryonic development prevents induction of smooth muscle actin in mesenchymal cells of the distal lung. In sum, these results demonstrate that Lfng functions to enhance Notch signaling in myofibroblast precursor cells and thereby to coordinate differentiation and mobilization of myofibroblasts required for alveolar septation.
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, 101 College St., East Tower, Rm. 14-309, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Keli
authors.initials: K
authors.lastname: Xu
authors.forename: Erica
authors.initials: E
authors.lastname: Nieuwenhuis
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Cohen
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Angelo J
authors.initials: AJ
authors.lastname: Canty
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Danska
authors.forename: Leigh
authors.initials: L
authors.lastname: Coultas
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
authors.forename: Megan Y J
authors.initials: MY
authors.lastname: Wu
authors.forename: Tino D
authors.initials: TD
authors.lastname: Piscione
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.forename: Achim
authors.initials: A
authors.lastname: Gossler
authors.forename: Geoff G
authors.initials: GG
authors.lastname: Hicks
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Hui
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.forename: Lisa X
authors.initials: LX
authors.lastname: Yu
authors.forename: John G
authors.initials: JG
authors.lastname: Sled
authors.forename: Thomas
authors.initials: T
authors.lastname: Gridley
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
mesh_terms: D000483:Alleles; D000818:Animals; D002454:Cell Differentiation; D003094:Collagen / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D016678:Genome / Q000235:genetics; D016695:Glycosyltransferases / Q000378:metabolism*; D007150:Immunohistochemistry; D008024:Ligands; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D055099:Neuroendocrine Cells / Q000378:metabolism / Q000473:pathology; D038081:Organogenesis; D011650:Pulmonary Alveoli / Q000002:abnormalities / Q000196:embryology* / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism
chemical_list: D008024:Ligands; D051880:Receptors, Notch; D003094:Collagen; D004549:Elastin; D016695:Glycosyltransferases; C498392:Lfng protein, mouse