Gas6 increases myelination by oligodendrocytes and its deficiency delays recovery following cuprizone-induced demyelination

PLoS One. 2011 Mar 10;6(3):e17727. doi: 10.1371/journal.pone.0017727.


Multiple sclerosis (MS) is a complex demyelinating disease of the central nervous system. Current research has shown that at least in some cases, the primary insult in MS could be directed at the oligodendrocyte, and that the earliest immune responses are primarily via innate immune cells. We have identified a family of receptor protein tyrosine kinases, known as the TAM receptors (Tyro3, Axl and Mertk), as potentially important in regulating both the oligodendrocyte and immune responses. We have previously shown that Gas6, a ligand for the TAM receptors, can affect the severity of demyelination in mice, with a loss of signalling via Gas6 leading to decreased oligodendrocyte survival and increased microglial activation during cuprizone-induced demyelination. We hypothesised TAM receptor signalling would also influence the extent of recovery in mice following demyelination. A significant effect of the absence of Gas6 was detected upon remyelination, with a lower level of myelination after 4 weeks of recovery in comparison with wild-type mice. The delay in remyelination was accompanied by a reduction in oligodendrocyte numbers. To understand the molecular mechanisms that drive the observed effects, we also examined the effect of exogenous Gas6 in in vitro myelination assays. We found that Gas6 significantly increased myelination in a dose-dependent manner, suggesting that TAM receptor signalling could be directly involved in myelination by oligodendrocytes. The reduced rate of remyelination in the absence of Gas6 could thus result from a lack of Gas6 at a critical time during myelin production after injury. These findings establish Gas6 as an important regulator of both CNS demyelination and remyelination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Axons / ultrastructure
  • Biomarkers / metabolism
  • Cell Lineage
  • Coculture Techniques
  • Cuprizone
  • Demyelinating Diseases / physiopathology*
  • Ganglia, Spinal / metabolism
  • Ganglia, Spinal / pathology
  • Intercellular Signaling Peptides and Proteins / deficiency*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / metabolism
  • Myelin Sheath / metabolism*
  • Myelin Sheath / pathology
  • Myelin Sheath / ultrastructure
  • Oligodendroglia / metabolism*
  • Oligodendroglia / pathology
  • Rats
  • Recovery of Function / physiology*
  • Time Factors


  • Biomarkers
  • Intercellular Signaling Peptides and Proteins
  • growth arrest-specific protein 6
  • Cuprizone