title: Early netrin-1 expression impairs central nervous system remyelination.
abstract: OBJECTIVE
  Chronically demyelinated multiple sclerosis (MS) lesions are frequently characterized by scarce undifferentiated oligodendrocyte progenitor cells (OPCs), suggesting the exhaustion of a local OPC pool followed by failure of recruitment and differentiation. Stimulating prompt OPC recruitment following demyelination could improve myelin repair by providing sufficient numbers of remyelinating cells during the repair-permissive period. Understanding mechanisms that determine this process may have important therapeutic implications. We therefore investigated the role of the guidance molecule netrin-1 in OPC recruitment and central nervous system (CNS) remyelination.
  
  
  METHODS
  Netrin-1 expression was analyzed immunohistochemically in different types of MS lesions and in the murine lysolecithin model of demyelination. The influence of netrin-1 on CNS remyelination was examined using gain and loss of function experiments.
  
  
  RESULTS
  We show that in MS lesions, astrocytes upregulate netrin-1 expression early during demyelination and netrin-1 receptors are expressed by OPCs. In contrast, in the efficiently repairing lysolecithin model of demyelination (astrocyte-free), netrin-1 expression is absent during early phases and detected concomitant with completion of OPC recruitment. In vitro migration assays demonstrated that netrin-1 is a chemorepellent for migrating adult OPCs. In mouse lesions, antibody-mediated disruption of netrin-1 function at the peak phase of recruitment increased OPC numbers. Conversely, lentiviral-mediated induction of netrin-1 expression prior to OPC recruitment reduced the number of cells recruited and impaired remyelination.
  
  
  CONCLUSIONS
  Our findings support the conclusion that netrin-1 expression within demyelinating MS plaques blocks OPC recruitment, which with repeated demyelinating episodes contributes to permanent remyelination failure.
authors.affiliation: Pierre and Marie Curie University, University of Paris 06, UM-75, Sorbonne Universities, ICM-GH Pitié-Salpêtrière, Paris, France; National Institute of Health and Medical Research (INSERM), U1127, Paris, France; National Center for Scientific Research (CNRS), Mixed Unit of Research 7225, Paris, France.
authors.forename: Vanja
authors.initials: V
authors.lastname: Tepavčević
authors.forename: Christophe
authors.initials: C
authors.lastname: Kerninon
authors.forename: Marie Stéphane
authors.initials: MS
authors.lastname: Aigrot
authors.forename: Elodie
authors.initials: E
authors.lastname: Meppiel
authors.forename: Sabah
authors.initials: S
authors.lastname: Mozafari
authors.forename: Raphaelle
authors.initials: R
authors.lastname: Arnould-Laurent
authors.forename: Philippe
authors.initials: P
authors.lastname: Ravassard
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kennedy
authors.forename: Brahim
authors.initials: B
authors.lastname: Nait-Oumesmar
authors.forename: Catherine
authors.initials: C
authors.lastname: Lubetzki
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology; D000075386:Netrin Receptors; D000075388:Netrin-1; D058953:Neural Stem Cells / Q000502:physiology*; D009836:Oligodendroglia / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1