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 RIS Download
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 | Transcription Factor HES-1 | Transcriptional Activation | Up-Regulation