PUBLICATION

Ephrin-A1-EphA4 signaling negatively regulates myelination in the central nervous system

Authors
Harboe, M., Torvund-Jensen, J., Kjaer-Sorensen, K., Laursen, L.S.
ID
ZDB-PUB-180120-10
Date
2018
Source
Glia   66(5): 934-950 (Journal)
Registered Authors
Keywords
EphA4, RhoA, axo-glia interaction, myelin, oligodendrocyte
MeSH Terms
  • Zebrafish
  • Signal Transduction
  • Cerebral Cortex/growth & development
  • Cerebral Cortex/metabolism
  • Zebrafish Proteins/metabolism
  • Rats
  • Animals
  • Coculture Techniques
  • rhoA GTP-Binding Protein/metabolism
  • Ephrin-A1/metabolism*
  • Animals, Genetically Modified
  • Axons/metabolism
  • Receptor, EphA4/metabolism*
  • Central Nervous System/growth & development*
  • Central Nervous System/metabolism*
  • Myelin Sheath/metabolism*
(all 16)
PubMed
29350423 Full text @ Glia
Abstract
During development of the central nervous system not all axons are myelinated, and axons may have distinct myelination patterns. Furthermore, the number of myelin sheaths formed by each oligodendrocyte is highly variable. However, our current knowledge about the axo-glia communication that regulates the formation of myelin sheaths spatially and temporally is limited. By using axon-mimicking microfibers and a zebrafish model system, we show that axonal ephrin-A1 inhibits myelination. Ephrin-A1 interacts with EphA4 to activate the ephexin1-RhoA-Rock-myosin 2 signaling cascade and causes inhibition of oligodendrocyte process extension. Both in myelinating co-cultures and in zebrafish larvae, activation of EphA4 decreases myelination, whereas myelination is increased by inhibition of EphA4 signaling at different levels of the pathway, or by receptor knockdown. Mechanistically, the enhanced myelination is a result of a higher number of myelin sheaths formed by each oligodendrocyte, not an increased number of mature cells. Thus, we have identified EphA4 and ephrin-A1 as novel negative regulators of myelination. Our data suggest that activation of an EphA4-RhoA pathway in oligodendrocytes by axonal ephrin-A1 inhibits stable axo-glia interaction required for generating a myelin sheath.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
zf2139TgTransgenic Insertion
    zf2140TgTransgenic Insertion
      1 - 2 of 2
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      Human Disease / Model
      No data available
      Sequence Targeting Reagents
      Target Reagent Reagent Type
      epha4aMO2-epha4aMRPHLNO
      epha4aMO3-epha4aMRPHLNO
      epha4bMO1-epha4bMRPHLNO
      epha4bMO2-epha4bMRPHLNO
      1 - 4 of 4
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      Fish
      Antibodies
      Orthology
      Engineered Foreign Genes
      Marker Marker Type Name
      Dendra2EFGDendra2
      mCherryEFGmCherry
      1 - 2 of 2
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      Mapping