Lunatic Fringe-mediated Notch signaling is required for lung alveogenesis

1 Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto; ; 2 Department of Mathematics and Statistics, McMaster University, Hamilton; and ; 3 Program in Genetics and Genome Biology, The Hospital for Sick Children, and Department of Immunology and Department of Medical Biophysics, Institute of Medical Sciences, University of Toronto, ; 4 Department of Molecular Genetics, University of Toronto, and ; 5 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; ; 6 Institute for Molecular Biology, Medizinische Hochschule Hannover, Hanover, Germany; ; 7 Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada; ; 8 Mouse Imaging Centre, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada; and ; 9 The Jackson Laboratory, Bar Harbor, Maine Submitted 6 November 2008 ; accepted in final form 12 October 2009 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 /+ ; RBPJ 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. alveolar development Address for reprint requests and other correspondence: S. E. Egan, 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 (e-mail: segan{at}sickkids.ca ).