The Neuregulin-Rac-MKK7 pathway regulates antagonistic c-jun/Krox20 expression in Schwann cell dedifferentiation

Glia. 2013 Jun;61(6):892-904. doi: 10.1002/glia.22482. Epub 2013 Mar 15.


Schwann cells respond to nerve injury by dedifferentiating into immature states and producing neurotrophic factors, two actions that facilitate successful regeneration of axons. Previous reports have implicated the Raf-ERK cascade and the expression of c-jun in these Schwann cell responses. Here we used cultured primary Schwann cells to demonstrate that active Rac1 GTPase (Rac) functions as a negative regulator of Schwann cell differentiation by upregulating c-jun and downregulating Krox20 through the MKK7-JNK pathway, but not through the Raf-ERK pathway. The activation of MKK7 and induction of c-jun in sciatic nerves after axotomy was blocked by Rac inhibition. Microarray experiments revealed that the expression of regeneration-associated genes, such as glial cell line-derived neurotrophic factor and p75 neurotrophin receptor, after nerve injury was dependent on Rac but not on ERK. Finally, the inhibition of ErbB2 signaling prevented MKK7 activation, c-jun induction, and Rac-dependent gene expression in sciatic nerve explant cultures. Taken together, our results indicate that the neuregulin-Rac-MKK7-JNK/c-jun pathway regulates Schwann cell dedifferentiation following nerve injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / pharmacology
  • Animals
  • Cell Dedifferentiation / drug effects
  • Cell Dedifferentiation / physiology*
  • Early Growth Response Protein 2 / metabolism*
  • MAP Kinase Kinase 7 / metabolism*
  • Mice
  • Neuregulin-1 / metabolism*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Pyrimidines / pharmacology
  • Schwann Cells / cytology
  • Schwann Cells / drug effects
  • Schwann Cells / metabolism*
  • Sciatic Nerve / cytology
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Aminoquinolines
  • Early Growth Response Protein 2
  • NSC 23766
  • Neuregulin-1
  • Proto-Oncogene Proteins c-jun
  • Pyrimidines
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase 7
  • Map2k7 protein, mouse