Elsevier

Neuropharmacology

Volume 110, Part B, November 2016, Pages 586-593
Neuropharmacology

Invited review
The roles of extracellular related-kinases 1 and 2 signaling in CNS myelination

https://doi.org/10.1016/j.neuropharm.2015.04.024Get rights and content

Highlights

  • Erk1/2 signalling regulates oligodendroglial survival, proliferation and differentiation.

  • Erk1/2 signalling regulates CNS myelination and remyelination.

  • Erk1/2 signalling cross talk with other pathways involved in CNS myelination.

  • Erk1/2 are potential activators of myelin-specific transcription factors.

Abstract

Substantial progress has been made in identifying the intracellular signaling pathways that regulate central nervous system myelination. Recently, the mitogen activated protein kinase pathway, in particular the extracellular signal-related kinase 1 (Erk1) and Erk2, have been identified as critically important in mediating the effects of several growth factors that regulate oligodendroglial development and myelination. Here we will review the recent studies that identify the key role that Erk1/2 signaling plays in regulating oligodendroglial development, myelination and remyelination, discuss the potential mechanisms that Erk1/2 may utilize to influence myelination, and highlight some questions for further research.

This article is part of the Special Issue entitled ‘Oligodendrocytes in Health and Disease’.

Introduction

Oligodendrocytes and Schwann cells are the myelin-forming glial cells in the central nervous system (CNS) and the peripheral nervous system (PNS), respectively. The axons of myelinated nerves are ensheathed by a concentrically wrapped multi-lamellar sheet of insulating plasma membrane comprised of specific proteins and lipids (Xiao et al., 2009). In the CNS, oligodendrocytes are responsible for the deposition of myelin internodes along the length of the axon. The myelin sheath not only confers increases in both the speed and efficiency of nerve impulse conduction along the axon, but also provides metabolic and trophic support for the axons (Nave and Trapp, 2008). In addition, new evidence suggests that myelin sheath may also mediate plastic changes in the brain that ultimately alters neural activity, synchrony and behavior (Nave and Werner, 2014). In demyelinating diseases such as multiple sclerosis, CNS myelin is attacked, damaged and removed, resulting in sporadic focal demyelinated lesions. The affected axons are left vulnerable to irreversible damage that ultimately determines the disease severity. Unless the myelin sheath is restored, the lack of trophic and metabolic support can result in permanent damage and ultimately neuronal death (Nave and Werner, 2014). The CNS has an endogenous capacity to remyelinate following a demyelinating insult, however over time and following successful demyelinating insults, remyelination is insufficient, leading to secondary irreversible axonal degeneration and neuronal loss (Franklin et al, 2012). Thus, understanding the molecular and cellular mechanisms that regulate myelination is critically important in order to develop new therapeutic strategies that directly target remyelination (Fancy et al., 2011a).

CNS myelination is a tightly regulated biological process. Recently, several intracellular signaling pathways have been shown to play key roles in mediating the transition of cells through the oligodendroglial lineage, and then to ultimately regulate the myelinating process (Ishii et al., 2013, Ishii et al., 2012, Xiao et al., 2012, Wood et al., 2013). Here we review the literature implicating the Erk1 and 2 (Erk1/2) pathways, and the roles they play in regulating myelination. We will focus on the evidence garnered from both in vitro and in vivo studies of Erk1/2 signaling in oligodendrocytes that regulate myelin development, as well as remyelination after injury. We also speculate about the potential mechanisms that Erk1/2 utilizes within the cytoplasm and/or nucleus to influence myelination, highlight some of the many questions that remain to be answered, and identify possibilities for further research.

Section snippets

Erk1/2 signaling

The kinases Erk1 and Erk2 are members of the mitogen-activated protein kinase (MAPK) family of protein kinases. They form part of a ubiquitously expressed and important signaling pathway which is involved in an array of cellular responses that ultimately alters gene expression to regulate critically important cellular processes such as survival, differentiation, proliferation. The kinases Erk1 and Erk2 share 84 percent amino acid identity and are often regarded as functionally equivalent (

Erk1/2 signaling in oligodendroglial development

During development, oligodendroglial cells arise from neuronal precursor cells, and must progress through several distinct stages within the oligoendroglial lineage before ultimately becoming a fully mature myelinating oligodendrocyte. Initially the cells exist as immature, proliferative oligodendrocyte progenitor cells (OPCs) which, when subjected to the appropriate external cues, will differentiate into mature, non-proliferative oligodendrocytes. Once these cells mature, they have a

Erk1/2 signaling in oligodendrocyte myelination

Recent in vivo and in vitro studies have shown Erk1/2 signalling within oligodendroglial cells is absolutely required for myelination, independent of oligodendroglial survival, proliferation or differentiation. Conditional deletion of Erk2 in radial glial cells, the cells that give rise to neurons, astrocytes and oligodendrocytes, led to a delay in CNS myelination during early postnatal development (Fyffe-Maricich et al., 2011). Adopting a more targeted model, conditional Erk2 deletion in OPCs

Erk1/2 signaling in CNS remyelination

The influence that Erk1/2 signalling exerts upon remyelination has been studied much less extensively. One recent study looked at the role of Erk1/2 activation in remyelination using the CA-MEK mouse, which expresses CA-MEK under the control of the CNP-Cre driver (Fyffe-Maricich et al., 2013). Like the other study using this mouse model (Ishii et al., 2013), these authors also observed thickening of the myelin sheath in spinal cord axons (Fyffe-Maricich et al., 2013). These authors then induced

Erk1/2 signaling in myelination – what is the mechanism?

Collectively, this growing body of work leads to the inescapable conclusion that activation of the MAPK pathway, and in particular Erk1/2, exerts a direct effect to specifically promote oligodendrocyte myelination. So, this begs the question of how does Erk1/2 achieve this?

  • (i)

    Cross-talk between Erk and Akt

Recently, several laboratories have identified a key role for the serine/threonine kinase Akt in promoting oligodendrocyte myelination. Transgenic overexpression of a CA-Akt mutant in

Conclusions and future perspectives

Myelination is a complex process, tightly controlled by both positive and negative factors. While recent evidence has consistently demonstrated that Erk1/2 is one of the dominant intracellular pathways within oligodendrocytes that regulate their capacity to myelinate, it is likely they are not acting in isolation, but rather part of a larger signaling network. Erk1/2 signaling is complex and able to exert influences on both cytoplasmic and nuclear proteins. The biological response to activation

References (86)

  • S.D. Kim

    Inhibition of GSK-3beta mediates expression of MMP-9 through ERK1/2 activation and translocation of NF-kappaB in rat primary astrocyte

    Brain Res.

    (2007)
  • E.M. Kramer

    Compartmentation of Fyn kinase with glycosylphosphatidylinositol-anchored molecules in oligodendrocytes facilitates kinase activation during myelination

    J. Biol. Chem.

    (1999)
  • T. Lee

    Docking motif interactions in MAP kinases revealed by hydrogen exchange mass spectrometry

    Mol. Cell.

    (2004)
  • H. Li

    Phosphorylation regulates OLIG2 cofactor choice and the motor neuron-oligodendrocyte fate switch

    Neuron

    (2011)
  • X. Liang

    The N-terminal SH4 region of the Src family kinase Fyn is modified by methylation and heterogeneous fatty acylation: role in membrane targeting, cell adhesion, and spreading

    J. Biol. Chem.

    (2004)
  • N. Liu

    ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes

    Lab. Invest

    (2005)
  • J.M. Newbern

    Specific functions for ERK/MAPK signaling during PNS development

    Neuron

    (2011)
  • R. Roskoski

    ERK1/2 MAP kinases: structure, function, and regulation

    Pharmacol. Res.

    (2012)
  • Y. Sun

    Phosphorylation state of Olig2 regulates proliferation of neural progenitors

    Neuron

    (2011)
  • X. Sun

    Rolipram promotes remyelination possibly via MEK-ERK signal pathway in cuprizone-induced demyelination mouse

    Exp. Neurol.

    (2012)
  • T.A. Watkins

    Distinct stages of myelination regulated by gamma-secretase and astrocytes in a rapidly myelinating CNS coculture system

    Neuron

    (2008)
  • V. Younes-Rapozo

    A role for the MAPK/ERK pathway in oligodendroglial differentiation in vitro: stage specific effects on cell branching

    Int. J. Dev. Neurosci.

    (2009)
  • F. Zassadowski

    Regulation of the transcriptional activity of nuclear receptors by the MEK/ERK1/2 pathway

    Cell. Signal

    (2012)
  • J. Zhang

    A bipartite mechanism for ERK2 recognition by its cognate regulators and substrates

    J. Biol. Chem.

    (2003)
  • S.Q. Zhang

    Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment

    Mol. Cell.

    (2004)
  • E. Aksamitiene et al.

    Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance

    Biochem. Soc. Trans.

    (2012)
  • K. Azim et al.

    GSK3beta negatively regulates oligodendrocyte differentiation and myelination in vivo

    Glia

    (2011)
  • R. Bansal et al.

    Specific inhibitor of FGF receptor signaling: FGF-2-mediated effects on proliferation, differentiation, and MAPK activation are inhibited by PD173074 in oligodendrocyte-lineage cells

    J. Neurosci. Res.

    (2003)
  • N.R. Bhat et al.

    Activation of mitogen-activated protein kinases in oligodendrocytes

    J. Neurochem.

    (1996)
  • A. Carracedo

    Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer

    J. Clin. Invest

    (2008)
  • L.-J. Chew

    Mechanisms of regulation of oligodendrocyte development by p38 mitogen-activated protein kinase

    J. Neurosci.

    (2010)
  • H. Colognato

    CNS integrins switch growth factor signalling to promote target-dependent survival

    Nat. Cell. Biol.

    (2002)
  • Q.-L. Cui et al.

    IGF-I-induced oligodendrocyte progenitor proliferation requires PI3K/Akt, MEK/ERK, and Src-like tyrosine kinases

    J. Neurochem.

    (2007)
  • Z.M. Dai

    Stage-specific regulation of oligodendrocyte development by Wnt/beta-catenin signaling

    J. Neurosci.

    (2014)
  • J. Dai et al.

    Interaction of mTOR and Erk1/2 signaling to regulate oligodendrocyte differentiation

    Glia

    (2014)
  • B. Emery

    Regulation of oligodendrocyte differentiation and myelination

    Science

    (2010)
  • S.P. Fancy

    Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS

    Genes. Dev.

    (2009)
  • S.P. Fancy

    Myelin regeneration: a recapitulation of development?

    Annu Rev. Neurosci.

    (2011)
  • S.P. Fancy

    Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination

    Nat. Neurosci.

    (2011)
  • K. Feigenson

    Canonical Wnt signalling requires the BMP pathway to inhibit oligodendrocyte maturation

    ASN Neuro

    (2011)
  • A.I. Flores

    Constitutively active Akt induces enhanced myelination in the CNS

    J. Neurosci.

    (2008)
  • R.J. Franklin

    Neuroprotection and repair in multiple sclerosis

    Nat. Rev. Neurol.

    (2012)
  • T.J. Frederick

    Synergistic induction of cyclin D1 in oligodendrocyte progenitor cells by IGF-I and FGF-2 requires differential stimulation of multiple signaling pathways

    Glia

    (2007)
  • Cited by (0)

    1

    Equal contribution to this paper.

    View full text