Activation of MAPK overrides the termination of myelin growth and replaces Nrg1/ErbB3 signals during Schwann cell development and myelination

Maria E Sheean, Erik McShane, Cyril Cheret, Jan Walcher, Thomas Müller, Annika Wulf-Goldenberg, Soraya Hoelper, Alistair N Garratt, Markus Krüger, Klaus Rajewsky, Dies Meijer, Walter Birchmeier, Gary R Lewin, Matthias Selbach, Carmen Birchmeier

Research output: Contribution to journalArticlepeer-review

Abstract

Myelination depends on the synthesis of large amounts of myelin transcripts and proteins and is controlled by Nrg1/ErbB/Shp2 signaling. We developed a novel pulse labeling strategy based on stable isotope labeling with amino acids in cell culture (SILAC) to measure the dynamics of myelin protein production in mice. We found that protein synthesis is dampened in the maturing postnatal peripheral nervous system, and myelination then slows down. Remarkably, sustained activation of MAPK signaling by expression of the Mek1DD allele in mice overcomes the signals that end myelination, resulting in continuous myelin growth. MAPK activation leads to minor changes in transcript levels but massively up-regulates protein production. Pharmacological interference in vivo demonstrates that the effects of activated MAPK signaling on translation are mediated by mTOR-independent mechanisms but in part also by mTOR-dependent mechanisms. Previous work demonstrated that loss of ErbB3/Shp2 signaling impairs Schwann cell development and disrupts the myelination program. We found that activated MAPK signaling strikingly compensates for the absence of ErbB3 or Shp2 during Schwann cell development and myelination.

Original languageEnglish
Pages (from-to)290-303
Number of pages14
JournalGenes & Development
Volume28
Issue number3
DOIs
Publication statusPublished - 1 Feb 2014

Keywords

  • Alleles
  • Animals
  • Cell Differentiation
  • Gene Expression Regulation
  • MAP Kinase Kinase 1
  • Mice
  • Microscopy, Electron, Transmission
  • Mitogen-Activated Protein Kinases
  • Multiprotein Complexes
  • Mutation
  • Myelin Sheath
  • Neuregulin-1
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Receptor, ErbB-3
  • Schwann Cells
  • Signal Transduction
  • TOR Serine-Threonine Kinases

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