Glial Membranes at the Node of Ranvier Prevent Neurite Outgrowth

Huang, Jeffrey K.; Phillips, Greg R.; Roth, Alejandro D.; Pedraza, Liliana; Shan, Weisong; Belkaïd, Wiam; Mi, Sha; Svenningsen, Åsa Fex; Florens, Laurence; Yates, John R.; Colman, David

doi:10.1126/science.1118313

Cited by 142 publications

(142 citation statements)

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“…For example, axons produce aberrant branches without the inhibitory effects of myelin. 52 The ordered arrangement of ion channels at the nodes of Ranvier (and therefore conductive properties of axons) also critically depends on correct myelination. 53 Oligodendrocytes are considered to be essential to long-term axonal integrity, potentially through trophic support mechanisms and axon−glia metabolic coupling mechanisms 54,55 leading to a widely held view that axon− myelin interactions have an important neuroprotective role (and by extension impact disease progression when perturbed).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Jenkins

Pickard

Khong

et al. 2013

ACS Chem. Neurosci.

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Corticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, "direct" action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus "indirect" action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses. Histological assessments showed no DEX effects on OPC proliferation or oligodendrocyte genesis/maturation (key processes underpinning myelin genesis). Immunostaining and RT-PCR analyses show that both cell types express glucocorticoid receptor (GR; the target for DEX action), ruling out receptor expression as a causal factor in the lack of DEX-responsiveness. GRs function as ligand-activated transcription factors, so we simultaneously analyzed DEX-induced transcriptional responses using microarray analyses; these substantiated the histological findings, with limited gene expression changes in DEX-treated OPCs and oligodendrocytes. With identical treatment, microglial cells showed profound and global changes post-DEX addition; an unexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsive gene in microglia. Our data indicate that CS-induced myelination delays are unlikely to be due to direct drug action on OPCs or oligodendrocytes, and may occur secondary to alterations in other neural cells, such as the immune component. To the best of our knowledge, this is the first comparative molecular and cellular analysis of CS effects in glial cells, to investigate the targets of this major class of anti-inflammatory drugs as a basis for myelination deficits.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Jenkins

Pickard

Khong

et al. 2013

ACS Chem. Neurosci.

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“…Interestingly, Nogo and NgR1 appear to play a role in closing the period of ocular dominance plasticity in mice (McGee et al, 2005). Furthermore, OMgp functions to restrict axonal sprouting from the Nodes of Ranvier as discussed above (Huang et al, 2005). Both of these two functions are in line with a general role in axonal plasticity for these neurite inhibitors in the absence of an injury.…”

Section: Physiological Function Of the Nogo/ngr1 Pathwaymentioning

confidence: 81%

“…Initially thought to be present in compact myelin, it was later shown that OMgp is expressed in the membrane surrounding the Nodes of Ranvier made by oligodendrocyte-like cells (Huang et al, 2005). Furthermore, most of OMgp expression appears to be in the neurons (Habib et al, 1998).…”

Section: Omgpmentioning

confidence: 99%

“…Furthermore, most of OMgp expression appears to be in the neurons (Habib et al, 1998). Interestingly, OMgp deficient mice exhibit elevated collateral sprouting from the CNS nodes of Ranvier, suggesting a more general role for OMgp in restricting axonal sprouting in development and physiology (Huang et al, 2005). However, a role for OMgp in adult CNS axon regeneration after injury has not been demonstrated.…”

Section: Omgpmentioning

confidence: 99%

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White matter inhibitors in CNS axon regeneration failure

Xie

Zheng

2008

Experimental Neurology

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Multiple lines of evidence have indicated that the inability of adult mammalian central nervous system (CNS) axons to regenerate after injury is partly due to the growth inhibitory property of central myelin. Three prototypical myelin-associated inhibitors of neurite outgrowth have been identified, including Nogo, myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp). These inhibitory ligands, their receptors and signaling pathways are being intensively investigated for their roles in CNS axon regeneration failure. In addition, several members of the axon guidance molecules have been implicated in restricting CNS axon regeneration, some of which are expressed by mature oligodendrocytes. Here we review in vitro and in vivo studies of these molecules in neurite growth and in axon regeneration failure and discuss the implications of these studies. While the increasing number of potential axon regeneration inhibitors highlights the complexity of the restrictive CNS environment, it provides new windows of opportunity as well as new challenges for therapeutic development for spinal cord injury and related neurological conditions.

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“…Perhaps these mechanisms operate on different spatial scales, with the PDGF signal operating over long distances to generally stimulate proliferation in an active axon fibre tract, while the glutamate signal is more spatially localised (due to efficient uptake by transporters) and inhibits proliferation when OPCs form a close apposition with an axon. If glutamate release from myelinated axons (Kriegler and Chiu, 1993) occurs from nodes of Ranvier, it might serve to tonically repress proliferation of OPCs, which have processes contacting the nodes (Butt et al, 1999) apparently in order to prevent axonal sprouting at that point (Huang et al, 2005). The glutamate released by action potentials may also regulate OPC migration (Wang et al, 1996;Gudz et al, 2006).…”

mentioning

confidence: 99%

Electrical signalling properties of oligodendrocyte precursor cells

2009

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yamina bakiri 1 , david attwell 1 and ragnhildur kara ' do ' ttir 2Oligodendrocyte precursor cells (OPCs) have become the focus of intense research, not only because they generate myelinforming oligodendrocytes in the normal CNS, but because they may be suitable for transplantation to treat disorders in which myelin does not form or is damaged, and because they have stem-cell-like properties in that they can generate astrocytes and neurons as well as oligodendrocytes. In this article we review the electrical signalling properties of OPCs, including the synaptic inputs they receive and their use of voltage-gated channels to generate action potentials, and we describe experiments attempting to detect output signalling from OPCs. We discuss controversy over the existence of different classes of OPC with different electrical signalling properties, and speculate on the lineage relationship and myelination potential of these different classes of OPC. Finally, we point out that, since OPCs are the main proliferating cell type in the mature brain, the discovery that they can develop into neurons raises the question of whether more neurons are generated in the mature brain from the classical sites of neurogenesis in the subventricular zone of the lateral ventricle and the hippocampal dentate gyrus or from the far more widely distributed OPCs.Keywords: Myelin, OPC, NG2, stem cell, neuron I N T R O D U C T I O NOligodendrocyte precursor cells (OPCs) transform into myelinating oligodendrocytes during development (Nishiyama et al., 2002), but are also present in the adult CNS where they comprise 5% of the cells and are the main proliferating cell type (Horner et al., 2000;Stallcup, 2002; Dawson et al., 2003). Damage to oligodendrocyte precursors, leading to reduced myelination, contributes to mental and physical impairment in periventricular leukomalacia (pre-or perinatal white matter injury leading to cerebral palsy; Volpe, 2001). Adult OPCs may form new myelinating oligodendrocytes in multiple sclerosis, and in brain or spinal cord injury (Levine, 1994;Gensert and Goldman, 1997;Keirstead et al., 1998;McTigue et al., 2001;Levine et al., 2001;Horner et al., 2002), and OPC transplants could serve as a basis for therapeutic remyelination (Windrem et al., 2008;Moreno-Manzano et al., 2009). This article will focus on the electrical signalling properties of OPCs which, as we will describe below, may play a crucial role in their development and their myelination of axons. D E F I N I N G O P C sIn the next section we will review several papers suggesting that OPCs are not a homogenous set of cells, but fall into at least two classes. To establish the range of properties of OPCs, it is essential to have criteria to define which cells are OPCs; so we will preface our review by examining the techniques available for doing this, and their advantages and pitfalls.Classically, OPCs have been defined antigenically, both in culture and in situ, by their expression of the proteoglycan NG2 (Nishiyama et al., 1996), the growth factor recept...

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Glial Membranes at the Node of Ranvier Prevent Neurite Outgrowth

Cited by 142 publications

References 31 publications

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

White matter inhibitors in CNS axon regeneration failure

Electrical signalling properties of oligodendrocyte precursor cells

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