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

Cell | Oct 17, 2003

http://www.ncbi.nlm.nih.gov/pubmed/14567914

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 RIS Download

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

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Associated grants

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

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