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

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.

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

“…Furthermore, ablation of Erk1/2 in Schwann cells causes deficits that are remarkably similar to those observed in Shp2 or Nrg1/ErbB2/ErbB3 mutants (Newbern et al, 2011). Interestingly, mild activation of MAPK signaling releases Schwann cells from their dependence of Nrg1 signaling during all stages of Schwann cell development and myelination (Sheean et al, 2014). In particular, MAPK/Erk positively regulate entry into myelination but a strong and sustained activation of Raf (and thus the Ras/MAPK/Erk cascade) results in demyelination, indicating that signaling strength determines the cellular response (Napoli et al, 2012).…”

“…Such studies mainly implicated PI3K/Akt as key signals in myelination, and suggested that MAPK/Erk played a limited role or even drive Schwann cells into dedifferentiation (Maurel and Salzer, 2000;Harrisingh et al, 2004;Ogata et al, 2006). Unexpectedly, recent genetic experiments have now shown that MAPK/Erk signaling is a major positive regulator of myelination in vivo, indicating that this notion has to be revisited (Grossmann et al, 2009;Newbern et al, 2011;Ishii et al, 2013;Sheean et al, 2014).…”

Myelination and mTOR

“…Although myelin proteins and lipids are probably overall relatively stable, in the long term they appear to be exchanged substantially according to a study conducted on human postmortem brain samples (Yeung et al, 2014). Of note, studies on myelin turnover in the PNS are rather scarce at this time and require further research attention (Sheean et al, 2014). …”

“…The major outcomes of the loss‐ and gain‐of‐function studies on the roles of mTORC1 and the upstream PI3K‐Akt and Mek‐Erk1/2 pathways in PNS and CNS myelination are summarized (Beirowski et al, 2017; Bercury et al, 2014; Carson et al, 2015; Cotter et al, 2010; Domenech‐Estevez et al, 2016; Figlia et al, 2017; Flores et al, 2008; Fyffe‐Maricich, Karlo, Landreth, & Miller, 2011; Fyffe‐Maricich, Schott, Karl, Krasno, & Miller, 2013; Goebbels et al, 2010, 2012; Ishii, Furusho, & Bansal, 2013; Ishii, Furusho, Dupree, & Bansal, 2016; Jeffries et al, 2016; Jiang et al, 2016; Lebrun‐Julien et al, 2014; Napoli et al, 2012; Newbern et al, 2011; Norrmén et al, 2014; Sheean et al, 2014; Sherman et al, 2012; Wahl et al, 2014; Zou et al, 2011, 2014)…”

“…Although the interpretation of the available evidence is somewhat complex due to variable experimental strategies used, the combined findings suggest that, in contrast to hyperactivation of mTORC1 following deletion of TSC1 or TSC2 (Beirowski et al, 2017; Carson et al, 2015; Figlia et al, 2017; Jiang et al, 2016; Lebrun‐Julien et al, 2014), hyperactivation of Mek‐Erk1/2 using constitutively active Mek1 causes radial hypermyelination, both in the CNS and PNS (Fyffe‐Maricich et al, 2013; Ishii et al, 2013, 2016; Sheean et al, 2014). However, the mTORC1‐independent targets of Mek‐Erk1/2 that may be responsible for the differences observed by activation of these signaling pathways are unknown.…”