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

Myelinationdepends on the synthesis of large amounts of myelintranscripts and proteins and is controlled by Nrg1/ ErbB/Shp2 signaling. We developed a novel pulse labelingstrategy based on stable isotope labelingwith amino acidsin cell culture(SILAC) to measure the dynamics of myelinprotein production in mice. We found that protein synthesis is dampened in the maturing postnatal peripheral nervous system, and myelinationthen 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 myelingrowth. 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 celldevelopment and disrupts the myelinationprogram. We found that activated MAPK signaling strikingly compensates for the absence of ErbB3or Shp2 during Schwann celldevelopment and myelination.