Inhibition of oligodendrocyte precursor cell differentiation by myelin-associated proteins

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Object

Promoting repair of central nervous system (CNS) white matter represents an important approach to easing the course of a number of tragic neurological diseases. For this purpose, strategies are currently being evaluated for transplanting cells capable of generating new oligodendrocytes into areas of demyelination and/or enhancing the potential of endogenous stem/precursor cells to give rise to new oligodendrocytes. Emerging evidence, however, indicates that increasing the presence of cells capable of forming new myelin sheaths is not sufficient to promote repair because of unknown inhibitors that accumulate in lesions as a consequence of myelin degeneration and impair the generation of new oligodendrocytes. The aim of the present study was to characterize the nature of the inhibitory molecules present in myelin.

Methods

Differentiation of primary rat oligodendrocyte precursor cells (OPCs) in the presence of CNS and peripheral nervous system myelin was assessed by immunocytochemical methods. The authors further characterized the nature of the inhibitors by submitting myelin membrane preparations to biochemical precipitation and digestion. Finally, OPCs were grown on purified Nogo-A, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein, the most prominent inhibitors of axon regeneration.

Results

Myelin membrane preparations induced a differentiation block in OPCs that was associated with down-regulation of expression of the transcription factor Nkx2.2. The inhibitory activity in myelin was restricted to the CNS and was predominantly associated with white matter. Furthermore, the results demonstrate that myelin proteins that are distinct from the most prominent inhibitors of axon outgrowth are specific inhibitors of OPC differentiation.

Conclusions

The inhibitory effect of unknown myelin-associated proteins should be considered in future treatment strategies aimed at enhancing CNS repair.

Abbreviations used in this paper:ANOVA = analysis of variance; CNS = central nervous system; MAG = myelin-associated glycoprotein; MAI = myelin-associated inhibitor; MPE = myelin protein extract; OMgp = oligodendrocyte myelin glycoprotein; OPC = oligodendrocyte precursor cell; PLL = poly-L-lysine; PNS = peripheral nervous system; SDS-PAGE = sodium dodecyl sulfate–polyacrylamide gel electrophoresis.

Object

Promoting repair of central nervous system (CNS) white matter represents an important approach to easing the course of a number of tragic neurological diseases. For this purpose, strategies are currently being evaluated for transplanting cells capable of generating new oligodendrocytes into areas of demyelination and/or enhancing the potential of endogenous stem/precursor cells to give rise to new oligodendrocytes. Emerging evidence, however, indicates that increasing the presence of cells capable of forming new myelin sheaths is not sufficient to promote repair because of unknown inhibitors that accumulate in lesions as a consequence of myelin degeneration and impair the generation of new oligodendrocytes. The aim of the present study was to characterize the nature of the inhibitory molecules present in myelin.

Methods

Differentiation of primary rat oligodendrocyte precursor cells (OPCs) in the presence of CNS and peripheral nervous system myelin was assessed by immunocytochemical methods. The authors further characterized the nature of the inhibitors by submitting myelin membrane preparations to biochemical precipitation and digestion. Finally, OPCs were grown on purified Nogo-A, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein, the most prominent inhibitors of axon regeneration.

Results

Myelin membrane preparations induced a differentiation block in OPCs that was associated with down-regulation of expression of the transcription factor Nkx2.2. The inhibitory activity in myelin was restricted to the CNS and was predominantly associated with white matter. Furthermore, the results demonstrate that myelin proteins that are distinct from the most prominent inhibitors of axon outgrowth are specific inhibitors of OPC differentiation.

Conclusions

The inhibitory effect of unknown myelin-associated proteins should be considered in future treatment strategies aimed at enhancing CNS repair.

The regeneration of myelin sheaths is increasingly recognized as an important therapeutic strategy for easing the devastating consequences of a variety of neurological disorders associated with injury to oligodendrocytes, including multiple sclerosis, spinal cord injury, and stroke. Remyelination in the CNS is mediated by a population of stem/precursor cells that traditionally have been referred to as “oligodendrocyte precursor cells” (OPCs). Numerous studies have demonstrated that white matter injury is, in principle, conducive to repair by the endogenous OPC population or by transplantation of exogenous OPCs.5,21 For unknown reasons, however, in human disease, myelin repair—commonly referred to as “remyelination”—is often disturbed and may become arrested at the step of OPC differentiation, leaving lesions containing oligodendrocyte lineage cells demyelinated and vulnerable to progressive axonal degeneration.8,20,58 Remyelination can restore function and saltatory signal conduction.26,48 As myelin sheaths also play an important role in axonal support,15,17,23,29,33 demyelinated axons are more vulnerable to injury.

One explanation for the failure of remyelination is the presence of inhibitors that accumulate in lesions as a consequence of the degeneration of myelin sheaths.27 Because inhibitors in myelin (MAIs) are able to prevent the differentiation of OPCs into mature oligodendrocytes,27,46 increasing the presence of OPCs may not be sufficient for promoting repair.

The molecular substrate responsible for the myelin-mediated differentiation block in OPCs is unknown. Myelin is formed by a complex aggregation of predominantly lipid and protein compounds. To design strategies for promoting myelin repair, it is crucial to understand the inhibitory substrate within lesions. In the present study we sought to determine the nature of the inhibitory molecules by assessing OPC differentiation in the presence of myelin substrates that were submitted to various biochemical precipitation and digestion steps and found that proteins enriched in white-matter preparations are potent inhibitors of OPC differentiation. Our results also demonstrate that MAIs induce a downregulation of Nkx2.2 expression, an important transcription factor for OPC differentiation. Finally, we show that the MAIs responsible for the OPC differentiation block differ from the most prominent myelin-associated inhibitors of axonal regeneration including Nogo-A, MAG, and OMgp.

Materials and Methods

Preparation and Purification of OPCs

Primary cultures of OPCs were isolated from P0–P2 neonatal Sprague–Dawley rat forebrains following a standard protocol.36 In brief, hemispheres were stripped free of meninges, after a digestion step the cells were plated into cell culture flasks, and mixed glia cultures were grown for ~ 10 days in Dulbecco modified Eagle medium supplemented with 10% fetal calf serum at 37°C in 7.5% CO2. The flasks were shaken for 1 hour at 260 rpm on an orbital shaker to remove the loosely attached microglia and were then shaken at 260 rpm overnight to dislodge the loosely attached oligodendrocyte precursors. The OPCs were further purified from contaminating microglia by a differential adhesion step. Subsequently the OPCs were plated onto PLL- or substrate-coated dishes. To maintain cells at an early precursor stage, platelet-derived growth factor-AA (PeproTech) and fibroblast growth factor (PeproTech) were added (10 ng/ml) to Sato medium. To induce differentiation, cells were incubated in Sato medium supplemented with 0.5% fetal calf serum. The purity of each culture was monitored following OPC purification by immunocyto-chemical analysis, and only cultures with > 95% purity were used.

Preparation of Myelin Membrane Substrates and MPEs

Myelin was purified by 2 rounds of discontinuous density gradient centrifugation and osmotic disintegration.42 The entire brains of young Sprague–Dawley rats were homogenized mechanically in ice-cold 0.32 M sucrose using a mechanical blender (Ultra-Turrax T18 basic, IKA Works). (Sucrose was dissolved in sterile 2.5 mM Tris/HCl, pH 7.0, to form 0.25, 0.32, and 0.88 M solutions.) The homogenate in 0.32 M sucrose solution was diluted with Tris/HCl to form a solution with a final molality of 0.25, which was then pelleted in an ultracentrifuge (55,000 × G, 4°C, 15 minutes). The pellet was resuspended in 0.88 M sucrose solution and overlaid with 0.25 M sucrose. After an ultracentrifugation step (100,000 × G, 4°C, 1 hour), the material at the interface was collected and washed in 30 ml of distilled H2O (55,000 × G, 4°C, 10 minutes). The pellet was resuspended in distilled H2O and incubated for 60 minutes on ice for osmotic disintegration. After centrifugation (55,000 × G, 4°C, 10 minutes), the flotation step was repeated. The material at the interface was collected and washed twice in distilled H2O (55,000 × G, 4°C, 10 minutes), and the pellet was stored at –80°C until isolation of the myelin protein.

To prepare MPE, the pellets were resuspended in 1% N-octyl β-D-glucopyranoside, 0.2 M sodium phosphate pH 6.8, 0.1 M Na2SO4, and 1 mM ethylenediaminetetraacetic acid and incubated at 23°C for 2 hours. Following ultracentrifugation (100,000 × G, 18°C, 30 minutes), the supernatant was collected and stored at –20°C until further use.1

Immunocytochemical Analysis

The OPCs were seeded at a density of 20,000 cells per well into PLL-coated 8-well chamber slides. After differentiating for 48 hours, the cells were fixed with 4% paraformaldehyde in phosphate-buffered saline and permeabilized and blocked with 0.3% Triton X-100 and 10% normal goat serum. The cells were then incubated with O4 antibody (1:100 dilution, Calbiochem) for 1 hour in the presence of 0.1% Triton X-100 and 2% normal goat serum, washed, and incubated for another 1 hour with the appropriate fluorescent secondary antibody (Cy3-conjugated antibody 1:100 dilution, Jackson ImmunoResearch).

Protein Precipitation of MPE

Enriched myelin proteins were precipitated with either a highly acidic organic solvent-based commercial kit (ProteoExtract Protein Precipitation Kit, Calbiochem) according to the manufacturer's instructions or a standard ammonium acetate–methanol precipitation. After overnight incubation at +4°C, precipitated protein pellets were washed extensively, and subsequently the proteins were incubated with either proteinase K (Sigma) or lipase (Sigma) for 1 hour at 37°C. The efficiency of digestion was confirmed by means of SDS-PAGE before the substrate was tested in our assay.

Preparation of Nogo-A, Nogo-A Δ20, MAG, and OMgp

Stable Nogo-A–transfected Chinese hamster ovary cells were kindly provided by Professor Martin E. Schwab. Cells were grown and selected with 250 μg/ml Zeocin (Invitrogen) until they reached confluence. After being rigorously washed with phosphate-buffered saline, they were lysed with lysis buffer, and recombinant proteins were purified over a Ni2+-NTA column (Qiagen) according to the manufacturer's protocol. Successful purification of Nogo-A was confirmed by Western blot analysis using Nogo-A monoclonal antibody 11C7 kindly provided by Professor Martin E. Schwab.

Bacterial Nogo-A Δ20 constructs were expressed in Escherichia coli and purified as described elsewhere.43 In brief, after growing in selective medium, the bacteria were lysed in lysis buffer and the supernatant was purified using the Co2+-Talon Metal Affinity Resin (Clontech). Similarly, OMgp was purified from constructs kindly provided by Dr. Zhigang He as well as obtained from a commercial source. Purified MAG was obtained from a commercial source.

Number of Experiments

Three independent experiments were conducted to determine O4 and Nkx2.2expression of OPCs on different concentrations of MPE substrates, as well as to determine the effects of MAG, Nogo-A and OMgp; 2 independent experiments were conducted to determine the inhibitory effects of PNS and CNS myelin, membrane preparations of white and gray CNS matter, and the effects of protease and lipase treatment.

Data Analysis

Data were analyzed using GraphPad Prizm software (Graph Pad). To test the concentration-dependent inhibition of OPC differentiation on MPE and the expression of Nkx2.2, we used a one-way ANOVA followed by the Dunnett post-test.

Results

Downregulation of Nkx2.2 Expression

In the course of our experiments we confirmed previous findings that demonstrated that CNS myelin membrane preparations are able to selectively arrest the differentiation of primary rat OPCs without affecting proliferation or cell death46 (data not included). The OPC differentiation block in vitro is associated with downregulation of O4, a surface marker present on early differentiating OPCs.46 An important regulator of OPC differentiation is the homeodomain transcription factor Nkx2.2.16,45 Our previous in vivo study demonstrated that failure of remyelination mediated by the addition of myelin membranes is associated with decreased Nkx2.2 expression.27 To test whether the in vitro system we adopted for our present study accurately reflects the findings in vivo, we assessed Nkx2.2 immunoreactivity on OPCs plated on myelin membrane preparations. Similar to the situation in vivo, MAIs induced a downregulation of Nkx2.2 in vitro ( Fig.1 ; p = 0.0036, one-way ANOVA).

Fig. 1.
Fig. 1.

Graph (a) and photomicrographs (b– d) illustrating that the presence of MAIs mediates changes in transcriptional regulation in OPCs. a: The Nkx2.2 immunoreactivity was downregulated in a concentration-dependent manner when OPCs were plated on myelin membrane preparations. Values shown are the means from 3 experiments. b: The OPCs were NKx2.2-positive after 48 hours of differentiation on PLL control substrates. c: Expression of Nkx2.2 was suppressed in OPCs grown on MPE after 48 hours. d: The same cells as in panel C stained with Hoechst. Bar = 30 μm.

Inhibition of OPC Differentiation

Myelin membrane preparations comprise a complex mixture of lipids and proteins, some of which are myelin-specific. As a first step in characterizing the substrate responsible for inhibiting OPC differentiation, we set out to investigate whether the inhibitory molecules can be solubilized from crude myelin membrane preparations by the use of detergents. We tested a number of different detergents and found that MPEs prepared with octyl-n-glucoside are able to induce an inhibition of OPC differentiation comparable to that of crude myelin membrane preparations. Oligodendrocyte precursor cells plated on MPE and cultured in differentiation medium for 48 hours displayed a concentration-dependent downregulation of O4 immunoreactivity (Fig. 2; p = 0.001, one-way ANOVA).

Fig. 2.
Fig. 2.

Graph (a), photomicrographs (b and c), and SDS-PAGE (d) illustrating the concentration-dependent differentiation block induced by MPEs in OPCs. a: Myelin protein extract induced a concentration-dependent downregulation of O4 expression after 48 hours' incubation in differentiation medium. Values are the means from 3 experiments. b: The OPCs on PLL control substrate demonstrated O4 immunoreactivity after 48 hours in differentiation medium. c: The O4 expression of OPCs plated on 200 μg myelin proteins was strongly suppressed. Cells are indicated by Hoechst nuclear stain. d: Coomassie-stained SDS-PAGE showed proteins extracted from myelin preparations with octyl-n-glucoside. Bar = 30 μm.

Previous results indicated that the inhibition of OPC differentiation is restricted to CNS myelin preparations and PNS preparations are not inhibitory.46 We confirmed these findings in our present study by culturing OPCs on substrates generated from pig CNS and PNS myelin (Fig. 3a). The application of density gradient–based separation protocols to whole brain extracts effectively enriches for myelin membranes,42,52,55 but the preparations thus obtained may well contain contaminants of cell membranes from other cell populations present in the CNS. To further specify the inhibitory molecules we took advantage of the distinct morphology of the brain that is characterized by white matter, which is mainly formed by myelin sheaths and axonal membranes, and gray matter, which is enriched with neuronal cell bodies. To evaluate whether the inhibitory molecules are more associated with CNS white matter or CNS gray matter, we plated OPCs onto extracts prepared from pig white and gray matter using the same protocol. Our results show that the peak of activity seems to lie within CNS white matter and that membrane preparations derived from CNS gray matter may be less inhibitory (Fig. 3b). Our results also indicate that the inhibitory substrate is conserved across species and not restricted to rodent CNS preparations.

Fig. 3.
Fig. 3.

Graphs illustrating that MAIs are not restricted to CNS myelin and are more associated with CNS white matter. a: Peripheral myelin did not affect OPC differentiation. b: The OPCs plated onto membrane substrates prepared from CNS gray matter were less inhibited than cells plated onto membrane preparations from CNS white matter. All substrates were prepared at 40 μg/cm; OPCs were incubated for 48 hours in differentiation medium. Values are the means from 2 experiments.

Myelin Protein as Inhibitor of OPC Differentiation

In a next step to remove lipids, salts, and small-molecule contaminants, MPE was submitted to 2 different protein precipitation steps: 1) a generic highly acidic organic solvent–based protocol (MPE-p[A]), and 2) an ammonium acetate/methanol–based protocol (MPE-p[B]). Subsequently the inhibitory activity was assessed. Neither treatment affected the inhibitory nature of the MPE, suggesting that the remaining protein was likely to be the source of the inhibition (Fig. 4). The notion that the inhibitory activity is associated with myelin protein was confirmed by an experiment in which the MPE precipitates thus prepared were subsequently treated with proteinase K, an enzyme that specifically disintegrates and destroys proteins. Treatment with proteinase K resulted in a loss of inhibitory activity; when MPE was incubated with lipase to destroy lipid components, however, the inhibitory activity remained unaltered.

Fig. 4.
Fig. 4.

Graph (a) and SDS-PAGE (b) illustrating that the inhibitory effects are associated with the protein component of myelin membrane preparations. a: The differentiation of OPCs plated on MPE and MPE precipitated by a highly acidic organic solvent–based protocol (MPE-p[A]) is strongly inhibited, whereas cells plated on control substrate (PLL) readily differentiate. Similarly, using an ammonium acetate/methanol– based precipitation method to remove lipid contaminants from MPE does not alter the inhibitory effects of MPE (MPE-p[B]). Disintegration of proteins with protease K eliminates the inhibitory effects of MPE (MPE-p[A/B]-proteinase K), while the inhibition remains active when lipids are degraded by incubation of MPE with triacylglycerol lipase (MPE-p[A/B]-lipase). b: Visualization of the protein content of each fraction demonstrates that proteins have been degraded successfully following protease treatment (MPE-p[A/B]-protease K), whereas they appear unaltered following incubation with lipases. All substrates were prepared with 40 μg protein/cm; OPCs cultured in differentiation medium for 48 hours.

Myelin Inhibitors of Axon Outgrowth

Myelin sheaths are characterized by a complex proteome52,55 containing several regeneration-inhibiting factors. The best-studied myelin proteins exerting inhibitory effects on CNS regenerative processes are those inhibiting axon regeneration.18 These include Nogo-A,9,22 MAG,37,40 and OMgp,28,57 which all bind the same axon receptor—NgR.12,19,32 The NgR has not been detected on OPCs, and its importance is uncertain, as several myelin inhibitory molecules transduce inhibitory signals from myelin to axons independent of this receptor.43,47,49,60,61 However, 2 other important coreceptors of inhibitory myelin proteins, LINGO-1 and p75NTR,57,59 are expressed on OPCs.7,14,44 Given these similarities, we sought to determine whether Nogo-A, MAG, and OMgp also control the inhibition of OPC differentiation.

To test whether the inhibitory effect of myelin is mediated by Nogo-A, we plated primary rat OPCs on purified total Nogo-A and Nogo-A Δ20, the main inhibitory domain of Nogo-A, expressed and purified from transduced bacteria or stably transfected Chinese hamser ovary cells.44 Similarly, OPCs were plated onto substrates prepared with purified MAG6 and OMgp,57 which are both potent inhibitors of axonal outgrowth. We found that none of the proteins tested negatively affected OPC differentiation. Thus, the proteins in myelin that inhibit OPC differentiation differ from the most prominent inhibitors of axon regeneration (Fig. 5).

Fig. 5.
Fig. 5.

Bar graphs showing that OPC differentiation remained unaffected when cells were cultured for 48 hours in differentiation medium on Nogo-A Δ20 (a), full-length Nogo-A (b), MAG (c), and OMgp (d). Values are the means from 3 experiments. Man = manual, signifying that the protein was purified from constructs.

Discussion

A number of different pathological conditions affect oligodendrocyte integrity. Injury to oligodendrocytes has been implicated in the well-recognized example of multiple sclerosis10,24,30,34 as well as such diverse conditions as schizophrenia,25,53 Alzheimer disease,3,41 and ischemia.11,35 Oligodendrocyte death is also an important feature of spinal cord injury,4,13,50 following which chronic progressive demyelination can occur.54 Whereas preventing oligodendrocyte cell death has beneficial effects on recovery following contusive spinal cord injury,51 the transplantation of OPCs improves the sparing of white matter as well as promoting functional recovery.2,31 Therapeutically enhancing remyelination thus promises to improve the course of a number of tragic neurological diseases.

Understanding the regulation of OPC differentiation during remyelination is critical to understanding the reasons for its failure and strategies by which it might be enhanced therapeutically. The reductionist approach that we have taken for our present study faithfully reproduces the findings of our in vivo study in which demyelinating lesions were supplemented with myelin membrane preparations.27 Similar to the situation in vivo, although OPCs are able to form processes, the presence of myelin potently inhibits the differentiation of OPCs into mature oligodendrocytes. The differentiation block occurring in both models is associated with a decrease in Nkx2.2 expression.

The results obtained in the present study emphasize the importance of environmental factors that are able to influence CNS repair. While the importance of these factors has been recognized with respect to axon regeneration for some time, our results specifically point to the fact that increasing the number of cells capable of repairing myelin sheaths by transplanting exogenous or promoting the recruitment of endogenous stem/precursor cells may not be sufficient to enhance remyelination. Instead, to be able to therapeutically promote myelin repair it may be necessary to identify the proteins responsible for the inhibitory effects on OPC differentiation and to acquire an understanding of the molecular mechanisms that mediate the differentiation block. We hope that, with this knowledge, it will become possible to devise efficient strategies for promoting remyelination.

An interesting point to note is that the known myelin inhibitors of axon growth that were tested in the present study (Nogo-A, MAG, and OMgp) did not affect OPC differentiation, although important coreceptors such as p75NTR and LINGO, which have been implicated in the recognition of Nogo-A, MAG, and OMgp38,56 in axonal growth cones, are also expressed by OPCs. Specifically, LINGO, an NgR coreceptor, has recently been recognized as a negative regulator of OPC differentiation;39 in OPCs, however, LINGO seems to be associated with an unknown receptor system.

Based on our findings, a number of strategies could be employed to detect the proteins in myelin that mediate inhibitory effects. As the proteome of myelin membrane preparations has been investigated in several studies,52,55 a promising approach consists of the use of biochemical separation techniques combined with subsequent mass spectrometry–based identification of protein species. Although we have demonstrated that proteins are involved in the inhibition, the possibility that complexes that entail proteins as well as glyco- or lipoproteins are responsible for the inhibition needs to be considered.

Conclusions

The presence of myelin-associated inhibitory proteins in acute lesions of various origin determines the efficiency of regeneration and should be considered when devising strategies that aim at enhancing white matter repair by promoting the response of endogenous OPCs or transplanting exogenous OPCs.

Acknowledgments

We thank Professor Martin E. Schwab of the Swiss Federal Institute of Technology (Eidgenössische Technische Hochschule Zurich) in Zurich, Switzerland, for the Nogo-A constructs; and Dr. Zhigang He of Children's Hospital and Harvard Medical School in Boston, Massachusetts, for the constructs for OMgp. We also thank Dr. Michael Sereda of the Max Planck Institute for Experimental Medicine in Göttingen, Germany, for his very helpful comments on the manuscript.

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    • Export Citation
  • 46

    Robinson SMiller RH: Contact with central nervous system myelin inhibits oligodendrocyte progenitor maturation. Dev Biol 216:3593681999

    • Search Google Scholar
    • Export Citation
  • 47

    Schweigreiter RWalmsley ARNiederöst BZimmermann DROertle TCasademunt E: Versican V2 and the central inhibitory domain of Nogo-A inhibit neurite growth via p75NTR/ NgR-independent pathways that converge at RhoA. Mol Cell Neurosci 27:1631742004

    • Search Google Scholar
    • Export Citation
  • 48

    Smith EJBlakemore WFMcDonald WI: Central remyelination restores secure conduction. Nature 280:3953961979

  • 49

    Song XYZhong JHWang XZhou XF: Suppression of p75NTR does not promote regeneration of injured spinal cord in mice. J Neurosci 24:5425462004

    • Search Google Scholar
    • Export Citation
  • 50

    Stirling DPKhodarahmi KLiu JMcPhail LTMcBride CBSteeves JD: Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J Neurosci 24:218221902004

    • Search Google Scholar
    • Export Citation
  • 51

    Tamura MNakamura MOgawa YToyama YMiura MOkano H: Targeted expression of anti-apoptotic protein p35 in oligodendrocytes reduces delayed demyelination and functional impairment after spinal cord injury. Glia 51:3123212005

    • Search Google Scholar
    • Export Citation
  • 52

    Taylor CMMarta CBClaycomb RJHan DKRasband MNCoetzee T: Proteomic mapping provides powerful insights into functional myelin biology. Proc Natl Acad Sci USA 101:464346482004

    • Search Google Scholar
    • Export Citation
  • 53

    Tkachev DMimmack MLRyan MMWayland MFreeman TJones PB: Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362:7988052003

    • Search Google Scholar
    • Export Citation
  • 54

    Totoiu MOKeirstead HS: Spinal cord injury is accompanied by chronic progressive demyelination. J Comp Neurol 486:3733832005

  • 55

    Vanrobaeys FVan Coster RDhondt GDevreese BVan Beeumen J: Profiling of myelin proteins by 2D-gel electrophoresis and multidimensional liquid chromatography coupled to MALDI TOF-TOF mass spectrometry. J Proteome Res 4:228322932005

    • Search Google Scholar
    • Export Citation
  • 56

    Wang KCKim JASivasankaran RSegal RHe Z: P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420:74782002

    • Search Google Scholar
    • Export Citation
  • 57

    Wang KCKoprivica VKim JASivasankaran RGuo YNeve RL: Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417:9419442002

    • Search Google Scholar
    • Export Citation
  • 58

    Wolswijk G: Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci 18:6016091998

    • Search Google Scholar
    • Export Citation
  • 59

    Wong STHenley JRKanning KCHuang KHBothwell MPoo MM: A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat Neurosci 5:130213082002

    • Search Google Scholar
    • Export Citation
  • 60

    Yamashita THiguchi HTohyama M: The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J Cell Biol 157:5655702002

    • Search Google Scholar
    • Export Citation
  • 61

    Zheng BAtwal JHo CCase LHe XLGarcia KC: Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo. Proc Natl Acad Sci USA 102:120512102005

    • Search Google Scholar
    • Export Citation

Article Information

Address correspondence to: Mark R. Kotter, M.D., Ph.D., Department of Neurosurgery, Georg-August Universität Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. email: mark.kotter@med.uni-goettingen.de.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Graph (a) and photomicrographs (b– d) illustrating that the presence of MAIs mediates changes in transcriptional regulation in OPCs. a: The Nkx2.2 immunoreactivity was downregulated in a concentration-dependent manner when OPCs were plated on myelin membrane preparations. Values shown are the means from 3 experiments. b: The OPCs were NKx2.2-positive after 48 hours of differentiation on PLL control substrates. c: Expression of Nkx2.2 was suppressed in OPCs grown on MPE after 48 hours. d: The same cells as in panel C stained with Hoechst. Bar = 30 μm.

  • View in gallery

    Graph (a), photomicrographs (b and c), and SDS-PAGE (d) illustrating the concentration-dependent differentiation block induced by MPEs in OPCs. a: Myelin protein extract induced a concentration-dependent downregulation of O4 expression after 48 hours' incubation in differentiation medium. Values are the means from 3 experiments. b: The OPCs on PLL control substrate demonstrated O4 immunoreactivity after 48 hours in differentiation medium. c: The O4 expression of OPCs plated on 200 μg myelin proteins was strongly suppressed. Cells are indicated by Hoechst nuclear stain. d: Coomassie-stained SDS-PAGE showed proteins extracted from myelin preparations with octyl-n-glucoside. Bar = 30 μm.

  • View in gallery

    Graphs illustrating that MAIs are not restricted to CNS myelin and are more associated with CNS white matter. a: Peripheral myelin did not affect OPC differentiation. b: The OPCs plated onto membrane substrates prepared from CNS gray matter were less inhibited than cells plated onto membrane preparations from CNS white matter. All substrates were prepared at 40 μg/cm; OPCs were incubated for 48 hours in differentiation medium. Values are the means from 2 experiments.

  • View in gallery

    Graph (a) and SDS-PAGE (b) illustrating that the inhibitory effects are associated with the protein component of myelin membrane preparations. a: The differentiation of OPCs plated on MPE and MPE precipitated by a highly acidic organic solvent–based protocol (MPE-p[A]) is strongly inhibited, whereas cells plated on control substrate (PLL) readily differentiate. Similarly, using an ammonium acetate/methanol– based precipitation method to remove lipid contaminants from MPE does not alter the inhibitory effects of MPE (MPE-p[B]). Disintegration of proteins with protease K eliminates the inhibitory effects of MPE (MPE-p[A/B]-proteinase K), while the inhibition remains active when lipids are degraded by incubation of MPE with triacylglycerol lipase (MPE-p[A/B]-lipase). b: Visualization of the protein content of each fraction demonstrates that proteins have been degraded successfully following protease treatment (MPE-p[A/B]-protease K), whereas they appear unaltered following incubation with lipases. All substrates were prepared with 40 μg protein/cm; OPCs cultured in differentiation medium for 48 hours.

  • View in gallery

    Bar graphs showing that OPC differentiation remained unaffected when cells were cultured for 48 hours in differentiation medium on Nogo-A Δ20 (a), full-length Nogo-A (b), MAG (c), and OMgp (d). Values are the means from 3 experiments. Man = manual, signifying that the protein was purified from constructs.

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    • Search Google Scholar
    • Export Citation
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    Robinson SMiller RH: Contact with central nervous system myelin inhibits oligodendrocyte progenitor maturation. Dev Biol 216:3593681999

    • Search Google Scholar
    • Export Citation
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    Schweigreiter RWalmsley ARNiederöst BZimmermann DROertle TCasademunt E: Versican V2 and the central inhibitory domain of Nogo-A inhibit neurite growth via p75NTR/ NgR-independent pathways that converge at RhoA. Mol Cell Neurosci 27:1631742004

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    • Export Citation
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    Smith EJBlakemore WFMcDonald WI: Central remyelination restores secure conduction. Nature 280:3953961979

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    • Search Google Scholar
    • Export Citation
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    Stirling DPKhodarahmi KLiu JMcPhail LTMcBride CBSteeves JD: Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. J Neurosci 24:218221902004

    • Search Google Scholar
    • Export Citation
  • 51

    Tamura MNakamura MOgawa YToyama YMiura MOkano H: Targeted expression of anti-apoptotic protein p35 in oligodendrocytes reduces delayed demyelination and functional impairment after spinal cord injury. Glia 51:3123212005

    • Search Google Scholar
    • Export Citation
  • 52

    Taylor CMMarta CBClaycomb RJHan DKRasband MNCoetzee T: Proteomic mapping provides powerful insights into functional myelin biology. Proc Natl Acad Sci USA 101:464346482004

    • Search Google Scholar
    • Export Citation
  • 53

    Tkachev DMimmack MLRyan MMWayland MFreeman TJones PB: Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362:7988052003

    • Search Google Scholar
    • Export Citation
  • 54

    Totoiu MOKeirstead HS: Spinal cord injury is accompanied by chronic progressive demyelination. J Comp Neurol 486:3733832005

  • 55

    Vanrobaeys FVan Coster RDhondt GDevreese BVan Beeumen J: Profiling of myelin proteins by 2D-gel electrophoresis and multidimensional liquid chromatography coupled to MALDI TOF-TOF mass spectrometry. J Proteome Res 4:228322932005

    • Search Google Scholar
    • Export Citation
  • 56

    Wang KCKim JASivasankaran RSegal RHe Z: P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420:74782002

    • Search Google Scholar
    • Export Citation
  • 57

    Wang KCKoprivica VKim JASivasankaran RGuo YNeve RL: Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417:9419442002

    • Search Google Scholar
    • Export Citation
  • 58

    Wolswijk G: Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci 18:6016091998

    • Search Google Scholar
    • Export Citation
  • 59

    Wong STHenley JRKanning KCHuang KHBothwell MPoo MM: A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat Neurosci 5:130213082002

    • Search Google Scholar
    • Export Citation
  • 60

    Yamashita THiguchi HTohyama M: The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J Cell Biol 157:5655702002

    • Search Google Scholar
    • Export Citation
  • 61

    Zheng BAtwal JHo CCase LHe XLGarcia KC: Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo. Proc Natl Acad Sci USA 102:120512102005

    • Search Google Scholar
    • Export Citation

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