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Transcriptional and Epigenetic Regulation of Oligodendrocyte Development and Myelination in the Central Nervous System

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Transcriptional and Epigenetic Regulation of Oligodendrocyte Development and Myelination in the Central Nervous System Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Transcriptional and Epigenetic Regulation of Oligodendrocyte Development and Myelination in the Central Nervous System Ben Emery1,2 and Q. Richard Lu3 1Department of Anatomy and Neurobiology, University of Melbourne, Victoria 3010, Australia 2Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria 3010, Australia 3Department of Pediatrics, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229 Correspondence: ben.emery@florey.edu.au; [email protected] Central nervous system (CNS) myelination by oligodendrocytes (OLs) is a highly orchestrated process involving well-defined steps from specification of neural stem cells into proliferative OL precursors followed by terminal differentiation and subsequent maturation of these pre- cursors into myelinating OLs. These specification and differentiation processes are mediated by profound global changes in gene expression, which are in turn subject to control by both extracellular signals and regulatory networks intrinsic to the OL lineage. Recently, basic transcriptional mechanisms that control OL differentiation and myelination have begun to be elucidated at the molecular level and on a genome scale. The interplay between tran- scription factors activated by differentiation-promoting signals and master regulators likely exerts a crucial role in controlling stage-specific progression of the OL lineage. In this review, we describe the current state of knowledge regarding the transcription factors and the epi- genetic programs including histone methylation, acetylation, chromatin remodeling, micro- RNAs, and noncoding RNAs that regulate development of OLs and myelination. long with neurons and astrocytes, oligoden- cesses, which occur on an ongoing basis during Adrocyte (OL) precursor cells (OPCs) arise both development and in adulthood, are medi- from multipotent neuroepithelial progenitor ated by equally dynamic changes in the expres- cells in the neurogenic niches of the developing sion and activity of transcription factors and and adult central nervous system (CNS). Once epigenetic programs. Perhaps more so than for specified, OPCs remain highly proliferative and any other CNS cell type, these transcriptional motile, dividing as they migrate out throughout and epigenetic programs have been mapped out the CNS. Once in their final position, they can for the OL lineage, using combinations of ex- undergo a terminal differentiation event before pression profiling, electroporation of the devel- myelinating adjacent axons (see Simons and oping neural tube, and knockout/transgenic ex- Nave 2015). These highly dynamic cellular pro- periments. More recently,genome-wide analysis Editors: Ben A. Barres, Marc R. Freeman, and Beth Stevens Additional Perspectives on Glia available at www.cshperspectives.org Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a020461 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a020461 1 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press B. Emery and Q.R. Lu of transcription factor binding, histone methyl- absolutely essential for specification to the OL ation, and acetylation patterns has been effec- lineage. Nevertheless, Olig2 most likely has a tively used to elucidate the direct targets and relatively broad role in promoting neural pre- relationships between key factors. This review cursors toward an OL fate, given forced expres- summarizes some of the major transcriptional sion of Olig2 either in the developing neural and epigenetic programs and key molecules that tube (Zhou et al. 2001; Liu et al. 2007) or cul- mediate development of the OL lineage and tured embryonic stem (ES) cells (Du et al. 2006) myelination in the CNS. promotes oligodendrogliogenesis. Like the pMN domain in general, Olig2 has a dual role in promoting both motor neuron TRANSCRIPTION FACTORS MEDIATING and OL fate. Phosphorylation of Olig2 at a ser- SPECIFICATION TO THE OL LINEAGE ine residue (Ser147) promotes motor neuron During both embryonic development and also specification, whereas, at later points in devel- within neurogenic niches in the adult, OPCs are opment, dephosphorylation at this site shifts specified from neuroepithelial precursor cells, the balance toward production of OLs, largely which also give rise to neurons and astrocytes. through sequestration of the proneural tran- The initial transcriptional control of specifica- scription factor Ngn2 (Li et al. 2011). More tion of neural progenitor cells to the OL lineage broadly, during development, several other is tightly related to the transcriptional control of transcription factors are involved in this neu- dorsoventral patterning of the neural tube, ral–glial switch throughout the nervous system. largely established by gradients of Sonic hedge- Ascl1 (also known as Mash1) appears to have a hog (Shh) and bone morphogenic proteins broad role in promoting specification to the OL (BMPs). During early development of the spi- lineage, as Ascl1 knockout mice display a severe nal cord, OPCs arise from the ventral pMN do- reduction in the number of OPCs (Parras et al. main, which gives rise first to motor neurons 2007; Sugimori et al. 2008). At early ages, Ascl1 and then to OPCs. This pMN domain is estab- promotes OL specification at the expense of lished and defined by the transcription factor neurons (Petryniak et al. 2007); at later ages, it Olig2, which is therefore essential for the gen- promotes OL specification at the expense of eration of these early ventrally derived OPCs generation of astrocytes (Nakatani et al. 2013). (Novitch et al. 2001; Zhou et al. 2001; Fu et al. Sox9 also promotes glial specification, includ- 2002; Lu et al. 2002; Zhou and Anderson 2002). ing to the OL lineage, as generation of OPCs is Less directly, other transcription factors that are substantially delayed in Sox9 conditional knock- involved in defining the borders of the pMN out embryos (Stolt et al. 2003). At least some of domain, such as Nkx6-1 (Liu et al. 2003) and Sox9’s gliogenic role is likely to be mediated Gli2 (Qi et al. 2003), also influence the produc- through its direct induction of the proglial/ tion of OPCs, as both the extent of the pMN antineuronal transcription factor nuclear factor domain and OPC specification are reduced in I/A (NFIA) (Kang et al. 2012), as Nfia null mice their absence. likewise display substantial reduction specifica- Although Olig2 is vital for this early ventral tion of neural progenitors to the OL lineage production of OPCs and is a consistent marker (Deneen et al. 2006). of the OL lineage, at later stages of embryogen- esis, OPCs also arise from more dorsal regions of the neural tube that do not initially express TRANSCRIPTION FACTORS IN OPCs Olig2 or the Nkx6 genes (Cai et al. 2005; Vall- Transcriptional Control of Maintenance stedt et al. 2005; Kessaris et al. 2006; Richardson of OPCs et al. 2006). Tosome extent, this probably reflects compensation by the closely related Olig1, es- Following their specification to the OL lineage, pecially within the hindbrain (Zhou and Ander- OPCs express a number of transcription factors son 2002), but it does suggest that Olig2 is not as they migrate from their birthplace to colonize 2 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a020461 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Oligodendrocyte and Myelination in the CNS the CNS. These included continued expression (bFGF) (Grinspan et al. 1996), there appears to of Olig1 and Olig2 as well as induced expression be little evidence of this occurring in vivo, of Nkx2-2 and Sox10. Electroporation of Olig2 where the OL differentiation step seems to be a expression vectors into the developing chick terminal event. As such, the differentiation step spinal cord strongly induces the expression of needs to be tightly controlled both to regulate both Nkx2-2 (Liu et al. 2007) and Sox10 (Zhou the timing of myelination during development et al. 2001; Liu et al. 2007), suggesting that Olig2 and to maintain a pool of OPCs capable of sub- acts to induce these two factors following spec- sequent division and differentiation through- ification. This was confirmed with the later dis- out life. covery that Olig2 directly targets upstream en- hancers of the Sox10 gene (Kuspert et al. 2011; Negative Regulators of Terminal Yu et al. 2013). Despite its early expression with- Differentiation in the OL lineage, Nkx2-2 does not appear to be vital for the maintenance of OPCs. Instead, OPCs express high levels of the transcription Nkx2-2 null mice show defects in the terminal factors Sox5, Sox6, Hes5, Id2, and Id4 (Fig. 1). differentiation of OPCs into OLs (Qi et al. 2001) Together, these factors mediate the influences of (see below), a finding consistent with the tran- inhibitory extracellular signals, which act on the sient up-regulation of Nkx2-2 protein observed OPCs to prevent their differentiation and mye- during differentiation (Fu et al. 2002). Similarly, lination. For example, Id2 and Id4 are down- despite the early expression of Sox10 in the lin- stream from the BMPs (Samanta and Kessler eage, mice lacking Sox10 display a relatively nor- 2004) and the antidifferentiation G protein– mal complement of OPCs (Stolt et al. 2002). coupled
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