Radical and lunatic fringes modulate notch ligands to support mammalian intestinal homeostasis

Elife. 2018 Apr 9:7:e35710. doi: 10.7554/eLife.35710.

Abstract

Notch signalling maintains stem cell regeneration at the mouse intestinal crypt base and balances the absorptive and secretory lineages in the upper crypt and villus. Here we report the role of Fringe family of glycosyltransferases in modulating Notch activity in the two compartments. At the crypt base, RFNG is enriched in the Paneth cells and increases cell surface expression of DLL1 and DLL4. This promotes Notch activity in the neighbouring Lgr5+ stem cells assisting their self-renewal. Expressed by various secretory cells in the upper crypt and villus, LFNG promotes DLL surface expression and suppresses the secretory lineage . Hence, in the intestinal epithelium, Fringes are present in the ligand-presenting 'sender' secretory cells and promote Notch activity in the neighbouring 'receiver' cells. Fringes thereby provide for targeted modulation of Notch activity and thus the cell fate in the stem cell zone, or the upper crypt and villus.

Keywords: Fringe; Glycosylation; Intestinal Crypts; Lgr5+ Stem Cell; Notch Signalling; cell biology; developmental biology; mouse; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Calcium-Binding Proteins
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Glucosyltransferases
  • Glycosyltransferases
  • Homeostasis*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intestines / cytology
  • Intestines / physiology*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proteins / physiology
  • Receptors, G-Protein-Coupled / physiology
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Signal Transduction
  • Stem Cells / cytology*
  • Stem Cells / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • DLL4 protein, mouse
  • Dlk1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Lgr5 protein, mouse
  • Membrane Proteins
  • Proteins
  • Receptors, G-Protein-Coupled
  • Receptors, Notch
  • Glycosyltransferases
  • Glucosyltransferases
  • Mfng protein, mouse
  • Rfng protein, mouse