Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis

Keli Xu, Erica Nieuwenhuis, Brenda L. Cohen, Wei Wang, Angelo J. Canty, Jayne S. Danska, Leigh Coultas, Janet Rossant, Megan Y.J. Wu, Tino D. Piscione, Andras Nagy, Achim Gossler, Geoff G. Hicks, Chi Chung Hui, R. Mark Henkelman, Lisa X. Yu, John G. Sled, Thomas Gridley, Sean E. Egan

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61 Citations (Scopus)

Abstract

Distal lung development occurs through coordinated induction of myofibroblasts, epithelial cells, and capillaries. Lunatic Fringe (Lfng) is a β 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 β-geo/+Notch3 β-geo/β-geo compound mutant mice but not in Notch2 β-geo/+or Notch3 β-geo/β-geo single mutants. Finally, to directly test for the role of Notch signaling in myofibroblast differentiation in vivo, we used ROSA26-rtTA /+;tetO-CRE /+;RBPJκ 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.

Original languageEnglish
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume298
Issue number1
DOIs
Publication statusPublished - Jan 2010
Externally publishedYes

Keywords

  • Alveolar development

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