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

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.

Pubmed ID: 14567914

Authors

  • Hu QD
  • Ang BT
  • Karsak M
  • Hu WP
  • Cui XY
  • Duka T
  • Takeda Y
  • Chia W
  • Sankar N
  • Ng YK
  • Ling EA
  • Maciag T
  • Small D
  • Trifonova R
  • Kopan R
  • Okano H
  • Nakafuku M
  • Chiba S
  • Hirai H
  • Aster JC
  • Schachner M
  • Pallen CJ
  • Watanabe K
  • Xiao ZC

Journal

Cell

Publication Data

October 17, 2003

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL32348
  • Agency: NHLBI NIH HHS, Id: HL35627
  • Agency: NCRR NIH HHS, Id: RR 15555

Mesh Terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • CHO Cells
  • Cell Adhesion Molecules, Neuronal
  • Cell Differentiation
  • Coculture Techniques
  • Contactins
  • Cricetinae
  • DNA-Binding Proteins
  • Dose-Response Relationship, Drug
  • HeLa Cells
  • Homeodomain Proteins
  • Humans
  • Ligands
  • Membrane Proteins
  • Models, Biological
  • Mutation
  • Myelin-Associated Glycoprotein
  • Oligodendroglia
  • Rats
  • Receptors, Cell Surface
  • Receptors, Notch
  • Recombinant Fusion Proteins
  • Signal Transduction
  • Transcriptional Activation
  • Up-Regulation