Signaling through ERK1/2 controls myelin thickness during myelin repair in the adult central nervous system

J Neurosci. 2013 Nov 20;33(47):18402-8. doi: 10.1523/JNEUROSCI.2381-13.2013.

Abstract

Oligodendrocytes, the myelin-forming cells of the CNS, exquisitely tailor the thickness of individual myelin sheaths to the diameter of their target axons to maximize the speed of action potential propagation, thus ensuring proper neuronal connectivity and function. Following demyelinating injuries to the adult CNS, newly formed oligodendrocytes frequently generate new myelin sheaths. Following episodes of demyelination such as those that occur in patients with multiple sclerosis, however, the matching of myelin thickness to axon diameter fails leaving remyelinated axons with thin myelin sheaths potentially compromising function and leaving axons vulnerable to damage. How oligodendrocytes determine the appropriate thickness of myelin for an axon of defined size during repair is unknown and identifying the signals that regulate myelin thickness has obvious therapeutic implications. Here, we show that sustained activation of extracellular-regulated kinases 1 and 2 (ERK1/2) in oligodendrocyte lineage cells results in accelerated myelin repair after injury, and is sufficient for the generation of thick myelin sheaths around remyelinated axons in the adult mouse spinal cord. Our findings suggest a model where ERK1/2 MAP kinase signaling acts as a myelin thickness rheostat that instructs oligodendrocytes to generate axon-appropriate quantities of myelin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / metabolism
  • Age Factors
  • Animals
  • Animals, Newborn
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Central Nervous System / pathology*
  • Demyelinating Diseases / chemically induced
  • Demyelinating Diseases / pathology*
  • Disease Models, Animal
  • Glial Fibrillary Acidic Protein / metabolism
  • MAP Kinase Kinase 1 / genetics
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Myelin Sheath / pathology*
  • Myelin Sheath / ultrastructure
  • Nerve Tissue Proteins / metabolism
  • Oligodendrocyte Transcription Factor 2
  • Oligodendroglia / metabolism
  • Polysaccharides / toxicity
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Up-Regulation / genetics
  • Up-Regulation / physiology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Glial Fibrillary Acidic Protein
  • Nerve Tissue Proteins
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2
  • Polysaccharides
  • MAP Kinase Kinase 1
  • Map2k1 protein, mouse
  • 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase