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1 The Hospital for Sick Children
2 McMaster University
3 Hospital for Scik Children
4 Unviversity of Toronto
5 Medizinische Hochschule Hannover
6 Faculty of Medicine, University of Manitoba
7 Hospital for Sick Children
8 The Jackson Laboratory
* To whom correspondence should be addressed. E-mail: segan{at}sickkids.ca.
Distal lung development occurs through coordinated induction of myofibroblasts, epithelial cells and capillaries. Lunatic Fringe (Lfng) is a
1-3 GlcNAc 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
-geo/+Notch3
-geo/
-geo compound mutant mice, but not in Notch2
-geo/+ or Notch3
-geo/
-geo single mutants. Finally, to directly test for the role of Notch signaling in myofibroblast differentiation in vivo we used ROSA26-rtTA/+;tetO-CRE/+;RBPJkflox/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.
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