Signaling by FGF Receptor 2, Not FGF Receptor 1, Regulates Myelin Thickness through Activation of ERK1/2–MAPK, Which Promotes mTORC1 Activity in an Akt-Independent Manner

Abstract

FGF signaling has emerged as a significant "late-stage" regulator of myelin thickness in the CNS, independent of oligodendrocyte differentiation. Therefore, it is critically important to identify the specific FGF receptor type and its downstream signaling molecules in oligodendrocytes to obtain better insights into the regulatory mechanisms of myelin growth. Here, we show that FGF receptor type 2 (FGFR2) is highly enriched at the paranodal loops of myelin. Conditional ablation of this receptor-type, but not FGF receptor type 1 (FGFR1), resulted in attenuation of myelin growth, expression of major myelin genes, key transcription factor Myrf and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) activity. This was rescued by upregulating ERK1/2 activity in these mice, strongly suggesting that ERK1/2 are key transducers of FGFR2 signals for myelin growth. However, given that the PI3K/Akt/mechanistic target of rapamycin (mTOR) pathway is also known to regulate myelin thickness, we examined FGFR2-deficient mice for the expression of key signaling molecules in this pathway. A significant downregulation of p-mTOR, p-Raptor, and p-S6RP was observed, which was restored to normal by elevating ERK1/2 activity in these mice. Similar downregulation of these molecules was observed in ERK1/2 knock-out mice. Interestingly, since p-Akt levels remained largely unchanged in these mice, it suggests a mechanism of mTORC1 activation by ERK1/2 in an Akt-independent manner in oligodendrocytes. Taken together, these data support a model in which FGFs, possibly from axons, activate FGFR2 in the oligodendrocyte/myelin compartment to increase ERK1/2 activation, which ultimately targets Myrf, as well as converges with the PI3K/Akt/mTOR pathway at the level of mTORC1, working together to drive the growth of the myelin sheath, thus increasing myelin thickness.

Independent and cooperative roles of the Mek/ERK1/2‐MAPK and PI3K/Akt/mTOR pathways during developmental myelination and in adulthood

“…We have recently shown that during active myelination, downregulation of myelin gene expression and myelin growth in conditional Erk1/2‐dKO mice is accompanied by a significant reduction in the expression of p‐mTOR, p‐Raptor, p‐p70S6K, and p‐S6RP, but not of p‐Akt. Since Akt is upstream of mTORC1 and p‐mTOR, p‐Raptor, p‐p70S6K, and p‐S6RP are traditionally considered downstream effectors in the PI3K/Akt/mTORC1 pathway, our earlier work suggested convergence of the two pathways at the level of mTORC1 (Figures and and Furusho et al, ). However, it was unclear whether the observed changes in the expression levels of these signaling molecules had any functional significance with respect to ERK1/2 signaling regulating myelin growth.…”

Axonal endoplasmic reticulum is very narrow

“…For Figs 1, 3 and 5, mouse tissues were fixed by cardiac perfusion of fixative, which consisted of 2.5% glutaraldehyde and 1% paraformaldehyde in 150 mM sodium cacodylate, pH 7.4 (all from Electron Microscopy Sciences, Hatfield, PA). The tissues were harvested as described for parotid salivary gland (Terasaki et al, 2013) and spinal cord (Furusho et al, 2017). The fixed tissues were processed by the ROTO protocol (Tapia et al, 2012), in which the tissue is incubated successively in reduced osmium, thiocarbohydrazide and unreduced osmium.…”

Myelination and mTOR

“…Although deletion of each of these proteins, or their cognate receptors, impaired OL myelination to some extent (Cellerino, Carroll, Thoenen, & Barde, 1997; Furusho, Ishii, & Bansal, 2017; Joseph D'Ercole & Ye, 2008; Kahn et al, 1999; Vondran, Clinton‐Luke, Honeywell, & Dreyfus, 2010; Ye, Li, Richards, DiAugustine, & D'Ercole, 2002; Zeger et al, 2007), it is unclear whether they are both necessary and sufficient to drive OL myelination, analogous to NRG1 type III in the PNS. The precise physiological cellular sources of these growth factors and the signals controlling their production and release are currently being elucidated.…”