A Central Role for the ERK-signaling Pathway in Controlling Schwann Cell Plasticity and Peripheral Nerve Regeneration in Vivo

Neuron. 2012 Feb 23;73(4):729-42. doi: 10.1016/j.neuron.2011.11.031.

Abstract

Following damage to peripheral nerves, a remarkable process of clearance and regeneration takes place. Axons downstream of the injury degenerate, while the nerve is remodeled to direct axonal regrowth. Schwann cells are important for this regenerative process. "Sensing" damaged axons, they dedifferentiate to a progenitor-like state, in which they aid nerve regeneration. Here, we demonstrate that activation of an inducible Raf-kinase transgene in myelinated Schwann cells is sufficient to control this plasticity by inducing severe demyelination in the absence of axonal damage, with the period of demyelination/ataxia determined by the duration of Raf activation. Remarkably, activation of Raf-kinase also induces much of the inflammatory response important for nerve repair, including breakdown of the blood-nerve barrier and the influx of inflammatory cells. This reversible in vivo model identifies a central role for ERK signaling in Schwann cells in orchestrating nerve repair and is a powerful system for studying peripheral neuropathies and cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Benzamides / pharmacology
  • Cell Movement / drug effects
  • Cyclin D1 / metabolism
  • Cytokines / metabolism
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Estrogen Antagonists / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Leukocytes / pathology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / physiology*
  • Male
  • Mast Cells / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Microscopy, Immunoelectron
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Myelin Sheath / genetics
  • Myelin Sheath / metabolism
  • Nerve Regeneration / drug effects
  • Nerve Regeneration / genetics*
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Peripheral Nerve Injuries / pathology
  • Peripheral Nerve Injuries / physiopathology*
  • Proto-Oncogene Proteins c-raf / genetics
  • Proto-Oncogene Proteins c-raf / metabolism*
  • Reaction Time / drug effects
  • Reaction Time / genetics
  • Receptor, Nerve Growth Factor / genetics
  • Receptor, Nerve Growth Factor / metabolism
  • Receptors, Estrogen / genetics
  • Recovery of Function / drug effects
  • Recovery of Function / genetics
  • Schwann Cells / physiology*
  • Schwann Cells / ultrastructure
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Tamoxifen / pharmacology
  • Time Factors

Substances

  • Benzamides
  • Cytokines
  • Estrogen Antagonists
  • PD 0325901
  • Receptor, Nerve Growth Factor
  • Receptors, Estrogen
  • Tamoxifen
  • Cyclin D1
  • Diphenylamine
  • Proto-Oncogene Proteins c-raf