Intracellular signaling pathway regulation of myelination and remyelination in the CNS

Abstract

The restoration of myelin sheaths on demyelinated axons remains a major obstacle in the treatment of multiple sclerosis (MS). Currently approved therapies work by modulating the immune system to reduce the number and rate of lesion formation but are only partially effective since they are not able to restore lost myelin. In the healthy CNS, myelin continues to be generated throughout life and spontaneous remyelination occurs readily in response to insults. In patients with MS, however, remyelination eventually fails, at least in part as a result of a failure of oligodendrocyte precursor cell (OPC) differentiation and the subsequent production of new myelin. A better understanding of the molecular mechanisms and signaling pathways that drive the process of myelin sheath formation is therefore important in order to speed the development of novel therapeutics designed to target remyelination. Here we review data supporting critical roles for three highly conserved intracellular signaling pathways: Wnt/β-catenin, PI3K/AKT/mTOR, and ERK/MAPK in the regulation of OPC differentiation and myelination both during development and in remyelination. Potential points of crosstalk between the three pathways and important areas for future research are also discussed.

Keywords: ERK MAPK; Intracellular signaling; Myelination; Oligodendrocyte development; PI3K/AKT; Remyelination; Wnt/β-catenin; mTOR.

Figure 1

Schematic representation of the (A) Wnt/β-catenin, (B) AKT/mTOR, (C) ERK/MAPK signaling networks that are important for oligodendrocyte development and myelination. Extracellular ligands are shown binding to their respective receptors to activate downstream signaling pathways. A detailed description of these interactions is provided in the text. Arrows indicate positive interactions and bars indicate inhibitory interactions. Black lines denote pathways described in oligodendrocytes, orange lines denote potential points of communication between the three pathways. Orange dotted lines denote interactions described in other cell types that may be conserved in oligodendrocytes. LRP5/6: Low density lipoprotein receptor-related protein 5 and 6, RTK: receptor tyrosine kinase, APC: adenomatous polyposis coli, CK1: casein kinase 1, GSK3β: glycogen synthase kinase 3-beta, CDK5: cyclin dependent kinase 5, mTOR: mechanistic target of rapamycin, mTORC: mechanistic target of rapamycin complex, PI3K: phosphoinositide-3-kinase, IRS-1: insulin receptor substrate 1, PIP2: phosphatidylinositol 4,5-bisphosphate, PIP3: phosphatidylinositol 3,4,5 trisphosphate, PTEN: phosphatase and tensin homolog, PDK1: 3-phosphoinositide-dependent protein kinase-1, TSC, tuberous sclerosis complex, Rheb: ras homolog enriched in brain, MEK: mitogen activated kinase kinase, ERK: extracellular signal related kinase, TCF/Lef: T-cell factor/lymphoid enhancer factor, SREB: sterol regulatory element-binding proteins, TF: transcription factors, HDAC: histone deacetylases