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.

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. SIGNIFICANCE STATEMENT It is well accepted that myelin is a biologically active membrane in active communication with the axons. However, the axonal signals, the receptors on myelin, and the integration of intracellular signaling pathways emanating downstream from these receptors that drive the growth of the myelin sheath remain poorly understood in the CNS. This study brings up the intriguing possibility that FGF receptor 2, in the oligodendrocyte/myelin compartment, may be one such signal. Importantly, it provides compelling evidence linking FGFR2 with the ERK1/2-MAPK pathway, which converges with the PI3K/Akt/mTOR (mechanistic target of rapamycin) pathway at the level of mTORC1 and also regulates the transcription factor Myrf, together providing a mechanistic framework for regulating both the transcriptional and translational machinery required for the proper growth of the myelin sheath.