ERK1/ERK2 MAPK signaling is required to increase myelin thickness independent of oligodendrocyte differentiation and initiation of myelination

J Neurosci. 2012 Jun 27;32(26):8855-64. doi: 10.1523/JNEUROSCI.0137-12.2012.

Abstract

Wrapping of the myelin sheath around axons by oligodendrocytes is critical for the rapid conduction of electrical signals required for the normal functioning of the CNS. Myelination is a multistep process where oligodendrocytes progress through a well coordinated differentiation program regulated by multiple extracellular growth and differentiation signals. The intracellular transduction of the extracellular signals that regulate myelination is poorly understood. Here we demonstrate a critical role for two important signaling molecules, extracelluar signal-regulated protein kinases 1 and 2 (ERK1/ERK2), downstream mediators of mitogen-activated protein kinases, in the control of CNS myelin thickness. We generated and analyzed two lines of mice lacking both ERK1/ERK2 function specifically in oligodendrocyte-lineage cells. In the absence of ERK1/ERK2 signaling NG2⁺ oligodendrocyte progenitor cells proliferated and differentiated on schedule. Mutant oligodendrocytes also ensheathed axons normally and made a few wraps of compact myelin. However, the subsequent increase in myelination that correlated myelin thickness in proportion to the axon caliber failed to occur. Furthermore, although the numbers of differentiated oligodendrocytes in the adult mutants were unchanged, they showed an inability to upregulate the transcription of major myelin genes that normally occurs during active myelination. Similarly, in vitro ERK1/ERK2-deficient oligodendrocytes differentiated normally but failed to form typical myelin-like membrane sheets. None of these effects were observed in single ERK1 or ERK2 mutants. These studies suggest that the predominant role of ERK1/ERK2 signaling in vivo is in promoting rapid myelin growth to increase its thickness, subsequent to oligodendrocyte differentiation and the initiation of myelination.

Publication types

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

MeSH terms

  • 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase
  • Age Factors
  • Animals
  • Antigens / genetics
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Female
  • MAP Kinase Signaling System / physiology*
  • Male
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Mitogen-Activated Protein Kinase 1 / deficiency
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / deficiency
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Mutation / genetics
  • Myelin Basic Protein / metabolism
  • Myelin Proteolipid Protein / genetics
  • Myelin Proteolipid Protein / metabolism
  • Myelin Sheath / genetics
  • Myelin Sheath / physiology*
  • Myelin Sheath / ultrastructure
  • Neurofilament Proteins / genetics
  • Neurofilament Proteins / metabolism
  • Neurons / metabolism
  • Neurons / ultrastructure
  • Oligodendroglia / metabolism
  • Oligodendroglia / ultrastructure
  • Organ Culture Techniques
  • Phosphoric Diester Hydrolases / genetics
  • Phosphorylation
  • Proteoglycans / genetics
  • RNA, Messenger / metabolism
  • Spinal Cord / cytology
  • Spinal Cord / metabolism

Substances

  • Antigens
  • Myelin Basic Protein
  • Myelin Proteolipid Protein
  • Neurofilament Proteins
  • Proteoglycans
  • RNA, Messenger
  • chondroitin sulfate proteoglycan 4
  • neurofilament protein M
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Phosphoric Diester Hydrolases
  • 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase
  • Cnp protein, mouse