Early netrin-1 expression impairs central nervous system remyelination

Ann Neurol. 2014 Aug;76(2):252-68. doi: 10.1002/ana.24201. Epub 2014 Jul 15.

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.

Interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Central Nervous System / metabolism*
  • Demyelinating Diseases / metabolism
  • Disease Models, Animal
  • Mice
  • Mice, Inbred C57BL
  • Nerve Growth Factors / metabolism*
  • Nerve Regeneration / physiology
  • Netrin Receptors
  • Netrin-1
  • Neural Stem Cells / physiology*
  • Oligodendroglia / physiology*
  • Receptors, Cell Surface / metabolism*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Nerve Growth Factors
  • Netrin Receptors
  • Ntn1 protein, mouse
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • Netrin-1