Invited reviewThe roles of extracellular related-kinases 1 and 2 signaling in CNS myelination
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?
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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
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