Activation of MAPK overrides the termination of myelin growth and replaces Nrg1/ErbB3 signals during Schwann cell development and myelination.
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.
Developmental Biology/Signal Transduction.
Maria E
ME
Sheean
Erik
E
McShane
Cyril
C
Cheret
Jan
J
Walcher
Thomas
T
Müller
Annika
A
Wulf-Goldenberg
Soraya
S
Hoelper
Alistair N
AN
Garratt
Markus
M
Krüger
Klaus
K
Rajewsky
Dies
D
Meijer
Walter
W
Birchmeier
Gary R
GR
Lewin
Matthias
M
Selbach
Carmen
C
Birchmeier
D000483:Alleles; D000818:Animals; D002454:Cell Differentiation; D005786:Gene Expression Regulation / Q000235:genetics; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046529:Microscopy, Electron, Transmission; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D046912:Multiprotein Complexes; D009154:Mutation; D009186:Myelin Sheath / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000166:cytology* / Q000648:ultrastructure; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D046912:Multiprotein Complexes; D020890:Neuregulin-1; D020893:Receptor, ErbB-3; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
MAPK; myelin; pSILAC; translational control