Full-Length and Fragmented Netrin-1 in Multiple Sclerosis Plaques Are Inhibitors of Oligodendrocyte Precursor Cell Migration

Oligodendrocytes exhibit a limited capacity to remyelinate in multiple sclerosis. Factors present in multiple sclerosis lesions are thought to inhibit oligodendrocyte precursor cell migration, limiting their recruitment to axons requiring remyelination; however, few inhibitors have been identified. A candidate inhibitor is netrin-1, a secreted protein that repels migrating oligodendrocyte precursor cells during neural development and is expressed by myelinating oligodendrocytes in the mature rodent central nervous system. Herein, we examined the distribution of netrin-1 in adult human white matter and multiple sclerosis lesions. We detected full-length netrin-1 protein and shorter netrin-1 fragments in samples of normal white matter and of multiple sclerosis lesions from adult human brain. We demonstrate that peptides corresponding to amino terminal domains VI and V of netrin-1 repel migrating oligodendrocyte precursor cells, but lack the chemoattractant activity of full-length netrin-1. Furthermore, recombinant domains VI-V of netrin-1 disrupt the chemoattractant activity of full-length netrin-1, consistent with a competitive mechanism of action. These findings indicate that full-length and fragmented forms of netrin-1, found in multiple sclerosis lesions, have the capacity to inhibit oligodendrocyte precursor migration, identifying netrin-1 as a potential target for therapies that promote remyelination. Oligodendrocytes exhibit a limited capacity to remyelinate in multiple sclerosis. Factors present in multiple sclerosis lesions are thought to inhibit oligodendrocyte precursor cell migration, limiting their recruitment to axons requiring remyelination; however, few inhibitors have been identified. A candidate inhibitor is netrin-1, a secreted protein that repels migrating oligodendrocyte precursor cells during neural development and is expressed by myelinating oligodendrocytes in the mature rodent central nervous system. Herein, we examined the distribution of netrin-1 in adult human white matter and multiple sclerosis lesions. We detected full-length netrin-1 protein and shorter netrin-1 fragments in samples of normal white matter and of multiple sclerosis lesions from adult human brain. We demonstrate that peptides corresponding to amino terminal domains VI and V of netrin-1 repel migrating oligodendrocyte precursor cells, but lack the chemoattractant activity of full-length netrin-1. Furthermore, recombinant domains VI-V of netrin-1 disrupt the chemoattractant activity of full-length netrin-1, consistent with a competitive mechanism of action. These findings indicate that full-length and fragmented forms of netrin-1, found in multiple sclerosis lesions, have the capacity to inhibit oligodendrocyte precursor migration, identifying netrin-1 as a potential target for therapies that promote remyelination. Netrin-1 is a secreted protein that regulates cell migration, process extension, and cell-cell adhesion during neural development.1Lai Wing Sun K. Correia J.P. Kennedy T.E. Netrins: versatile extracellular cues with diverse functions.Development. 2011; 138: 2153-2169Crossref PubMed Scopus (311) Google Scholar Oligodendrocytes, the myelinating glia of the central nervous system (CNS), respond to netrin-1 during several stages of their development. In the embryonic spinal cord, netrin-1 signals through its receptors deleted in colorectal cancer (DCC) and the Unc5 homologues2Moore S.W. Tessier-Lavigne M. Kennedy T.E. Netrins and their receptors.Adv Exp Med Biol. 2007; 621: 17-31Crossref PubMed Scopus (167) Google Scholar to repel migrating oligodendrocyte precursor cells (OPCs) away from the ventral ventricular zone.3Jarjour A.A. Manitt C. Moore S.W. Thompson K.M. Yuh S.J. Kennedy T.E. Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord.J Neurosci. 2003; 23: 3735-3744PubMed Google Scholar, 4Sugimoto Y. Taniguchi M. Yagi T. Akagi Y. Nojyo Y. Tamamaki N. Guidance of glial precursor cell migration by secreted cues in the developing optic nerve.Development. 2001; 128: 3321-3330PubMed Google Scholar, 5Tsai H.H. Tessier-Lavigne M. Miller R.H. Netrin 1 mediates spinal cord oligodendrocyte precursor dispersal.Development. 2003; 130: 2095-2105Crossref PubMed Scopus (98) Google Scholar As oligodendrocytes mature, netrin-1 promotes the extension and elaboration of processes6Rajasekharan S. Baker K.A. Horn K.E. Jarjour A.A. Antel J.P. Kennedy T.E. Netrin 1 and Dcc regulate oligodendrocyte process branching and membrane extension via Fyn and RhoA.Development. 2009; 136: 415-426Crossref PubMed Scopus (96) Google Scholar via DCC-dependent activation of fyn and inhibition of RhoA.7Rajasekharan S. Bin J.M. Antel J.P. Kennedy T.E. A central role for RhoA during oligodendroglial maturation in the switch from netrin-1 mediated chemorepulsion to process elaboration.J Neurochem. 2010; 113: 1589-1597PubMed Google Scholar In the mature CNS, netrin-1 promotes the maintenance of axo-oligodendroglial paranodal junctions made by myelinating oligodendrocytes.8Jarjour A.A. Bull S.J. Almasieh M. Rajasekharan S. Baker K.A. Mui J. Antel J.P. Di Polo A. Kennedy T.E. Maintenance of axo-oligodendroglial paranodal junctions requires DCC and netrin-1.J Neurosci. 2008; 28: 11003-11014Crossref PubMed Scopus (48) Google Scholar, 9Manitt C. Colicos M.A. Thompson K.M. Rousselle E. Peterson A.C. Kennedy T.E. Widespread expression of netrin-1 by neurons and oligodendrocytes in the adult mammalian spinal cord.J Neurosci. 2001; 21: 3911-3922Crossref PubMed Google Scholar Although the roles for netrin-1 in the rodent CNS are well established, only a few studies have addressed the functional significance of netrin-1 in the human CNS. Herein, we assess the distribution of netrin-1 protein associated with intact white matter and multiple sclerosis (MS) lesions in the adult human brain. MS is characterized by multifocal demyelination and axonal loss. Although remyelination does occur in MS, the extent is often limited.10Goldschmidt T. Antel J. Konig F.B. Bruck W. Kuhlmann T. Remyelination capacity of the MS brain decreases with disease chronicity.Neurology. 2009; 72: 1914-1921Crossref PubMed Scopus (275) Google Scholar, 11Patani R. Balaratnam M. Vora A. Reynolds R. Remyelination can be extensive in multiple sclerosis despite a long disease course.Neuropathol Appl Neurobiol. 2007; 33: 277-287Crossref PubMed Scopus (228) Google Scholar Remyelination of MS lesions is attributed to differentiation of endogenous OPCs, rather than previously myelinating oligodendrocytes.12Gensert J.M. Goldman J.E. Endogenous progenitors remyelinate demyelinated axons in the adult CNS.Neuron. 1997; 19: 197-203Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar, 13Miron V.E. Kuhlmann T. Antel J.P. Cells of the oligodendroglial lineage, myelination, and remyelination.Biochim Biophys Acta. 2011; 1812: 184-193Crossref PubMed Scopus (183) Google Scholar Local factors in MS lesions that inhibit OPC recruitment or their subsequent differentiation into oligodendrocytes are implicated in contributing to the inability of OPCs to remyelinate efficiently.14Piaton G. Williams A. Seilhean D. Lubetzki C. Remyelination in multiple sclerosis.Prog Brain Res. 2009; 175: 453-464Crossref PubMed Scopus (51) Google Scholar, 15Miller R.H. Mi S. Dissecting demyelination.Nat Neurosci. 2007; 10: 1351-1354Crossref PubMed Scopus (98) Google Scholar Previous studies have identified inhibitors of OPC migration during remyelination, including the chemorepellent guidance cue, Semaphorin-3A; however, the influence of inhibitors of OPC migration on remyelination is not well understood.16Piaton G. Aigrot M.S. Williams A. Moyon S. Tepavcevic V. Moutkine I. Gras J. Matho K.S. Schmitt A. Soellner H. Huber A.B. Ravassard P. Lubetzki C. Class 3 semaphorins influence oligodendrocyte precursor recruitment and remyelination in adult central nervous system.Brain. 2011; 134: 1156-1167Crossref PubMed Scopus (123) Google Scholar, 17Williams A. Piaton G. Aigrot M.S. Belhadi A. Theaudin M. Petermann F. Thomas J.L. Zalc B. Lubetzki C. Semaphorin 3A and 3F: key players in myelin repair in multiple sclerosis?.Brain. 2007; 130: 2554-2565Crossref PubMed Scopus (170) Google Scholar The role of netrin-1 as a repellent for migrating OPCs during development3Jarjour A.A. Manitt C. Moore S.W. Thompson K.M. Yuh S.J. Kennedy T.E. Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord.J Neurosci. 2003; 23: 3735-3744PubMed Google Scholar, 4Sugimoto Y. Taniguchi M. Yagi T. Akagi Y. Nojyo Y. Tamamaki N. Guidance of glial precursor cell migration by secreted cues in the developing optic nerve.Development. 2001; 128: 3321-3330PubMed Google Scholar, 5Tsai H.H. Tessier-Lavigne M. Miller R.H. Netrin 1 mediates spinal cord oligodendrocyte precursor dispersal.Development. 2003; 130: 2095-2105Crossref PubMed Scopus (98) Google Scholar and its expression by neurons and glia in the mature CNS9Manitt C. Colicos M.A. Thompson K.M. Rousselle E. Peterson A.C. Kennedy T.E. Widespread expression of netrin-1 by neurons and oligodendrocytes in the adult mammalian spinal cord.J Neurosci. 2001; 21: 3911-3922Crossref PubMed Google Scholar suggest that it might also influence OPC migration and remyelination in MS. Herein, we report readily detectable levels of netrin-1 protein in human adult normal control white matter (NCWM) and in chronic MS lesions. In addition to full-length netrin-1 protein, fragments of netrin-1 were detected in both types of tissue. We show that fragments containing the amino terminal domain VI of netrin-1 effectively repel migrating OPCs, but have lost chemoattractant function. These findings provide evidence that full-length and fragmented forms of netrin-1 protein present in MS lesions may impede remyelination by inhibiting OPC migration, thereby limiting the access of these cells to demyelinated axons. Sprague-Dawley rat pups were obtained from Charles River Canada (Senneville, QC, Canada). All procedures were performed in accordance with the Canadian Council on Animal Care guidelines. OPCs isolated from mixed glial cultures derived from the cerebral cortices of postnatal day 0 rat pups were grown in oligodendrocyte-defined medium, as previously described.3Jarjour A.A. Manitt C. Moore S.W. Thompson K.M. Yuh S.J. Kennedy T.E. Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord.J Neurosci. 2003; 23: 3735-3744PubMed Google Scholar, 18Armstrong R.C. Isolation and characterization of immature oligodendrocyte lineage cells.Methods. 1998; 16: 282-292Crossref PubMed Scopus (70) Google Scholar Tissue was obtained from surgical resections performed to treat non–tumor-related intractable epilepsy in accordance with the Biomedical Ethics Unit of McGill University (Montreal, QC, Canada) guidelines. Mature oligodendrocytes were isolated as previously described,19Miron V.E. Jung C.G. Kim H.J. Kennedy T.E. Soliven B. Antel J.P. FTY720 modulates human oligodendrocyte progenitor process extension and survival.Ann Neurol. 2008; 63: 61-71Crossref PubMed Scopus (228) Google Scholar and 105 cells per well were plated in 16-well poly-l-lysine–coated glass-chamber slides (Nalge Nunc International, Naperville, IL) in minimal essential medium with 5% fetal calf serum, 1% penicillin-streptomycin, 1% glutamine, and 0.1% glucose. The enrichment of OPCs in these cultures has been previously characterized.20Wosik K. Antel J. Kuhlmann T. Bruck W. Massie B. Nalbantoglu J. Oligodendrocyte injury in multiple sclerosis: a role for p53.J Neurochem. 2003; 85: 635-644Crossref PubMed Scopus (76) Google Scholar Truncated chicken netrin-1, containing domains VI and V with a c-terminal myc tag, was generated and purified, as previously described.21Kennedy T.E. Wang H. Marshall W. Tessier-Lavigne M. Axon guidance by diffusible chemoattractants: a gradient of netrin protein in the developing spinal cord.J Neurosci. 2006; 26: 8866-8874Crossref PubMed Scopus (131) Google Scholar The netrin-1 domain VI was generated by PCR amplification of the N-terminal sequence of netrin-1, ending in YAVSDLQVGG, and cloning into the pFUSE-hFc1 expression vector (Invitrogen, CA), which encodes a c-terminal human Fc, to generate a netrin-1 domain VI–human Fc fusion protein. The cDNA was expressed in HEK293T cells and purified using protein A/G affinity beads (Santa Cruz Biotechnology, Santa Cruz, CA). Primary antibodies used were rabbit Santa Cruz rabbit C. Colicos M.A. Thompson K.M. Rousselle E. Peterson A.C. Kennedy T.E. Widespread expression of netrin-1 by neurons and oligodendrocytes in the adult mammalian spinal cord.J Neurosci. 2001; 21: 3911-3922Crossref PubMed Google Scholar CA), rat rat protein rabbit protein chicken protein University of protein and E. University of cells were with and in and Canada) for 1 full-length netrin-1 and netrin-1 were using and with netrin-1 Truncated netrin-1 are c-terminal of in to a c-terminal Fc netrin VI-V ending with netrin ending in netrin ending in and netrin ending in We MS lesions from obtained from the Tissue the and University of All lesions were characterized by extensive demyelination and was to the was derived from or to and as activation and and were obtained in accordance with the of of Brain Tissue of or or and for for MS. in a MS. were with and was performed with activity was by with 5% in for Tissue was in fetal calf in for by was performed for and brain samples were obtained from with MS or CNS disease from the Tissue of The studies were performed in accordance with the McGill University MS and samples were from with and that were with few or were identified as of was in 1% 0.1% and with inhibitors and using a Canada) for samples were by and OPC migration were performed as previously described.3Jarjour A.A. Manitt C. Moore S.W. Thompson K.M. Yuh S.J. Kennedy T.E. Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord.J Neurosci. 2003; 23: 3735-3744PubMed Google Scholar OPCs were plated on a with were to the of the cells were with and 0.1% Cells that to the of the were by of OPCs were for and and for and The of cells per well was and with the control was from of embryonic day rat spinal cord in a as previously T.E. T. Tessier-Lavigne M. Netrins are diffusible factors for axons in the embryonic spinal Full Text PDF PubMed Scopus Google Scholar HEK293T cells were 105 cells per well in a Cells were for and with of both and F. F. C. C. C. S. C. P. with of netrin-1 receptors cell 2009; 16: PubMed Scopus Google Scholar using (Invitrogen, CA), to the Cells were with netrin-1 or netrin-1 domain VI-V protein for by with and 0.1% with inhibitors and was performed by of with cell and protein were isolated using a protein A/G by in and with were by and the of were detected by using and rabbit was performed using CA), as K.E. D. Bull S.J. T. J. D. M. E. P. A. G. Kennedy T.E. DCC expression by neurons regulates in the adult Full Text Full Text PDF PubMed Scopus Google Scholar are as significance was using of by netrin-1 expression in human white we human mature to their rodent C. Colicos M.A. Thompson K.M. Rousselle E. Peterson A.C. Kennedy T.E. Widespread expression of netrin-1 by neurons and oligodendrocytes in the adult mammalian spinal cord.J Neurosci. 2001; 21: 3911-3922Crossref PubMed Google Scholar netrin-1 and netrin We found that adult human oligodendrocytes in netrin-1, as well as the netrin-1 DCC and In of from adult human detected netrin-1 protein associated with oligodendrocyte and cell and We examined the distribution of netrin-1 protein in chronic demyelinated lesions from MS to oligodendrocyte and cell were netrin-1 in MS lesions and white matter We also detected and for netrin-1 associated with the extracellular of lesions. of protein the of full-length netrin-1 in both and MS lesions A and and In addition to the full-length protein, multiple to were netrin-1 is of N-terminal domains to the N-terminal domains VI and V of and of a S. Kennedy T.E. The netrin protein Biol. 2009; 10: PubMed Scopus Google Scholar antibodies netrin-1, in domains VI and V in and detected the was detected in control using antibodies that the were to the fragments of netrin-1 be we purified recombinant netrin-1 the of both domains VI and V and the of only domain VI to studies using full-length A.A. Manitt C. Moore S.W. Thompson K.M. Yuh S.J. Kennedy T.E. Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord.J Neurosci. 2003; 23: 3735-3744PubMed Google Scholar purified recombinant domain VI-V and domain VI repellent activity for rodent OPCs in a migration of domain VI-V or domain VI not influence OPC that the of migrating cells was not of OPC We that domain VI of netrin-1 is to a chemorepellent by OPCs in that fragments of netrin-1 in may repel migrating cells and to inhibiting the recruitment of OPCs to demyelinated MS with chronic lesions containing inhibitors of OPC migration, as netrin-1, we that the MS oligodendrocytes with the white matter Although recombinant domain VI-V migrating OPCs, it was to of embryonic spinal cord, a of to netrin-1 T.E. T. Tessier-Lavigne M. Netrins are diffusible factors for axons in the embryonic spinal Full Text PDF PubMed Scopus Google Scholar Furthermore, of netrin-1 with domain VI-V the chemoattractant activity of full-length netrin-1, consistent with a competitive We in the of its netrin-1 the but not activity of full-length netrin-1. has previously been that domain VI-V both DCC and K. M. Tessier-Lavigne M. in colorectal cancer (DCC) encodes a netrin Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. Tessier-Lavigne M. of C. are candidate netrin 1997; PubMed Scopus Google however, in addition to to requires of DCC E. Y. M. Tessier-Lavigne M. of DCC by netrin-1 to guidance of 2001; PubMed Scopus Google Scholar We domain VI-V it does not DCC it to we full-length and in HEK293T cells, by of these cells for with netrin-1 or domain using antibodies of associated with of full-length netrin-1 with consistent with of DCC by netrin-1 and In of domain VI-V not DCC We that the netrin-1 is for DCC and that the inability of domain VI-V to DCC the of chemoattractant findings indicate that netrin-1 is present in human and MS lesions, associated with oligodendrocytes and In MS lesions, were also netrin-1 and the extracellular of netrin-1 distribution may from the of netrin-1 into the the of myelin and the of it be by or in the extracellular Netrin-1 is also expressed by isolated from Wang W. G. Netrin-1 regulates and through and 2010; PubMed Scopus Google recruitment of these cells to MS lesions may to the netrin-1 protein cell including OPCs and mature both DCC and Unc5 which a netrin-1 that mediates chemorepellent to A. of in guidance in Biol. 1998; PubMed Scopus Google Scholar, K. M. Tessier-Lavigne M. E. A domains of and DCC receptors to Full Text Full Text PDF PubMed Scopus Google Scholar, K. and by the Unc5 netrin 2001; Full Text Full Text PDF PubMed Scopus Google Scholar Previous studies that OPCs are by a gradient of netrin-1, migrating away from of netrin-1 in and away from the in the embryonic spinal cord in A.A. Manitt C. Moore S.W. Thompson K.M. Yuh S.J. Kennedy T.E. Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord.J Neurosci. 2003; 23: 3735-3744PubMed Google Scholar, 5Tsai H.H. Tessier-Lavigne M. Miller R.H. Netrin 1 mediates spinal cord oligodendrocyte precursor dispersal.Development. 2003; 130: 2095-2105Crossref PubMed Scopus (98) Google Scholar In these in studies that OPCs with a of netrin-1 OPC A.A. Manitt C. Moore S.W. Thompson K.M. Yuh S.J. Kennedy T.E. Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord.J Neurosci. 2003; 23: 3735-3744PubMed Google Scholar in addition to the of a gradient of netrin-1, netrin-1 also a on OPCs, inhibiting their of migration in the of a A.A. Manitt C. Moore S.W. Thompson K.M. Yuh S.J. Kennedy T.E. Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord.J Neurosci. 2003; 23: 3735-3744PubMed Google Scholar these findings suggest that in the of a distribution of netrin-1, as is the in MS lesions, netrin-1 is to inhibit OPC migration, limiting remyelination. Although the of netrin-1 in lesions may have a on remyelination, it might a role in with MS. Previous studies have netrin-1 to have in several including and Wang W. G. Netrin-1 regulates and through and 2010; PubMed Scopus Google Scholar, W. G. Netrin-1 and netrin-1 injury of the 2008; PubMed Scopus Google Scholar, C. R. G. Netrin-1 regulates the of and and injury by inhibiting PubMed Scopus Google Scholar, C. G. the injury and by PubMed Scopus Google Scholar, M. J. H. guidance netrin-1 cell during PubMed Scopus Google Scholar, Y. Y. Wang H. Y. W. Y. W. Netrin-1 and PubMed Scopus Google Scholar, V. D. C. Konig K. P. Netrin-1 2011; PubMed Scopus Google Scholar, V. S. C. M.A. J. K.E. D. P. Netrin-1 during Care 2010; PubMed Scopus Google Scholar, C. V. P. K. Konig K. T. G. P. The guidance protein netrin-1 in a of 2010; PubMed Scopus Google Scholar Although the mechanism by which netrin-1 regulates roles in inhibiting cell C. R. G. Netrin-1 regulates the of and and injury by inhibiting PubMed Scopus Google Scholar, M. J. 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These fragments are not disease were present in samples from both control and with MS. We have previously a in the expression of netrin-1 during the postnatal maturation of the rat spinal C. Colicos M.A. Thompson K.M. Rousselle E. Peterson A.C. Kennedy T.E. Widespread expression of netrin-1 by neurons and oligodendrocytes in the adult mammalian spinal cord.J Neurosci. 2001; 21: 3911-3922Crossref PubMed Google Scholar is the of the N-terminal domains VI and V of netrin-1 amino with the netrin-1 antibodies used to in domains VI and V of netrin-1 of netrin-1 that of the amino of domain VI has been in a of cell C. D. A. G. S. S. M. A. P. of a netrin-1 cell PubMed Scopus Google however, of netrin-1 that in the of shorter netrin-1 has not been in the CNS or normal tissue. on we that the netrin-1 peptides detected are fragments of full-length netrin-1 that of domains VI and V. the of fragmented netrin-1, we generated and purified recombinant netrin-1 peptides corresponding to domains VI and V or only domain the capacity of full-length netrin-1 to repel migrating OPCs in We that the netrin-1 may not be to present in however, findings provide evidence that peptides present in that domain VI may repel migrating that the of full-length and fragmented netrin-1 in the extracellular of MS lesions inhibit OPCs from migrating into of Previous studies have that recombinant protein of domains VI and V of netrin-1 is to the of both DCC and K. M. Tessier-Lavigne M. in colorectal cancer (DCC) encodes a netrin Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. Tessier-Lavigne M. of C. are candidate netrin 1997; PubMed Scopus Google Scholar despite both we demonstrate domain VI-V is to a chemorepellent the chemoattractant activity of full-length netrin-1 has been of DCC is for E. Y. M. Tessier-Lavigne M. of DCC by netrin-1 to guidance of 2001; PubMed Scopus Google Scholar We have that in the of the netrin-1 its to DCC The has been to of a netrin-1 that the domain M. W. A of the netrin with the of and functional Biol. PubMed Scopus Google Scholar We that the lack of the netrin-1 netrin-1 DCC which the of chemoattractant In of a has that is netrin-1 domain VI-V protein is via fusion to a human K. M. Tessier-Lavigne M. in colorectal cancer (DCC) encodes a netrin Full Text Full Text PDF PubMed Scopus Google Scholar In addition to the of chemoattractant domain VI-V protein the capacity of netrin-1 to promote DCC-dependent that it with full-length netrin-1 for DCC in addition to OPCs, netrin-1 fragments detected in may also disrupt the of intact full-length netrin-1. findings show that full-length and fragmented netrin-1, extracellular that myelin and A.A. Manitt C. Moore S.W. Thompson K.M. Yuh S.J. Kennedy T.E. Netrin-1 is a chemorepellent for oligodendrocyte precursor cells in the embryonic spinal cord.J Neurosci. 2003; 23: 3735-3744PubMed Google Scholar, 5Tsai H.H. Tessier-Lavigne M. Miller R.H. Netrin 1 mediates spinal cord oligodendrocyte precursor dispersal.Development. 2003; 130: 2095-2105Crossref PubMed Scopus (98) Google Scholar, S. Baker K.A. Horn K.E. Jarjour A.A. Antel J.P. Kennedy T.E. Netrin 1 and Dcc regulate oligodendrocyte process branching and membrane extension via Fyn and RhoA.Development. 2009; 136: 415-426Crossref PubMed Scopus (96) Google Scholar, A.A. Bull S.J. Almasieh M. Rajasekharan S. Baker K.A. Mui J. Antel J.P. Di Polo A. Kennedy T.E. Maintenance of axo-oligodendroglial paranodal junctions requires DCC and netrin-1.J Neurosci. 2008; 28: 11003-11014Crossref PubMed Scopus (48) Google Scholar are present in adult human white as well as in demyelinated MS lesions, are to inhibit OPC of netrin-1 may remyelination in with MS of the of netrin-1 associated with the extracellular in lesions. Although netrin-1 and netrin-1 fragments may a role in the mature CNS by cell migration, and K. M. F. Tessier-Lavigne M. Netrin-1 is a inhibitor to Neurosci. 2008; 28: PubMed Scopus Google Scholar, C. Thompson K.M. Kennedy T.E. in expression of netrin receptors in the rat spinal of in Res. PubMed Scopus Google Scholar, C. Wang D. Kennedy T.E. to netrin-1 and netrin expression spinal cord Res. 2006; PubMed Scopus Google Scholar findings indicate that inhibit the capacity of OPCs to access and repair demyelinated in the development of to netrin-1 for of as MS. We for on the

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