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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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CHO Cells
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Cell Adhesion Molecules, Neuronal / metabolism*
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Cell Adhesion Molecules, Neuronal / pharmacology
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Cell Differentiation
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Coculture Techniques
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Contactins
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Cricetinae
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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HeLa Cells
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Homeodomain Proteins / metabolism
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Humans
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Ligands
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Models, Biological
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Mutation
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Myelin-Associated Glycoprotein / metabolism
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Oligodendroglia / cytology
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Oligodendroglia / physiology*
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Rats
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Receptors, Cell Surface / metabolism
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Receptors, Notch
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Recombinant Fusion Proteins / metabolism
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Signal Transduction
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Transcription Factor HES-1
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Transcriptional Activation
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Ubiquitin-Protein Ligases
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Up-Regulation
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Cell Adhesion Molecules, Neuronal
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Contactins
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DNA-Binding Proteins
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Hes1 protein, mouse
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Hes1 protein, rat
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Homeodomain Proteins
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Ligands
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Membrane Proteins
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Myelin-Associated Glycoprotein
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Receptors, Cell Surface
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Receptors, Notch
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Recombinant Fusion Proteins
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Transcription Factor HES-1
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HES1 protein, human
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Dtx1 protein, mouse
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Ubiquitin-Protein Ligases