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

Early netrin-1 expression impairs central nervous system remyelination.

Author information

1
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.

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.

PMID:
24942777
DOI:
10.1002/ana.24201
[Indexed for MEDLINE]

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