F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation

Cell. 2003 Oct 17;115(2):163-75. doi: 10.1016/s0092-8674(03)00810-9.

Abstract

Axon-derived molecules are temporally and spatially required as positive or negative signals to coordinate oligodendrocyte differentiation. Increasing evidence suggests that, in addition to the inhibitory Jagged1/Notch1 signaling cascade, other pathways act via Notch to mediate oligodendrocyte differentiation. The GPI-linked neural cell recognition molecule F3/contactin is clustered during development at the paranodal region, a vital site for axoglial interaction. Here, we show that F3/contactin acts as a functional ligand of Notch. This trans-extracellular interaction triggers gamma-secretase-dependent nuclear translocation of the Notch intracellular domain. F3/Notch signaling promotes oligodendrocyte precursor cell differentiation and upregulates the myelin-related protein MAG in OLN-93 cells. This can be blocked by dominant negative Notch1, Notch2, and two Deltex1 mutants lacking the RING-H2 finger motif, but not by dominant-negative RBP-J or Hes1 antisense oligonucleotides. Expression of constitutively active Notch1 or Notch2 does not upregulate MAG. Thus, F3/contactin specifically initiates a Notch/Deltex1 signaling pathway that promotes oligodendrocyte maturation and myelination.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • CHO Cells
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Cell Adhesion Molecules, Neuronal / pharmacology
  • Cell Differentiation
  • Coculture Techniques
  • Contactins
  • Cricetinae
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • HeLa Cells
  • Homeodomain Proteins / metabolism
  • Humans
  • Ligands
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Biological
  • Mutation
  • Myelin-Associated Glycoprotein / metabolism
  • Oligodendroglia / cytology
  • Oligodendroglia / physiology*
  • Rats
  • Receptors, Cell Surface / metabolism
  • Receptors, Notch
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Transcription Factor HES-1
  • Transcriptional Activation
  • Ubiquitin-Protein Ligases
  • Up-Regulation

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Adhesion Molecules, Neuronal
  • Contactins
  • DNA-Binding Proteins
  • Hes1 protein, mouse
  • Hes1 protein, rat
  • Homeodomain Proteins
  • Ligands
  • Membrane Proteins
  • Myelin-Associated Glycoprotein
  • Receptors, Cell Surface
  • Receptors, Notch
  • Recombinant Fusion Proteins
  • Transcription Factor HES-1
  • HES1 protein, human
  • Dtx1 protein, mouse
  • Ubiquitin-Protein Ligases