Multiple sclerosis: Re-expression of a developmental pathway that restricts oligodendrocyte maturation

Gareth R. John, Sai Latha Shankar, Bridget Shafit-Zagardo, Aldo Massimi, Sunhee C. Lee, Cedric S. Raine, Celia F. Brosnan

Research output: Contribution to journalArticle

376 Scopus citations

Abstract

During mammalian central nervous system (CNS) development, contact-mediated activation of Notch1 receptors on oligodendrocyte precursors by the ligand Jagged1 induces Hes5, which inhibits maturation of these cells. Here we tested whether the Notch pathway is re-expressed in the adult CNS in multiple sclerosis (MS), an inflammatory demyelinating disease in which remyelination is typically limited. We found that transforming growth factor-β1 (TGF-β1), a cytokine upregulated in MS, specifically re-induced Jagged1 in primary cultures of human astrocytes. Within and around active MS plaques lacking remyelination, Jagged1 was expressed at high levels by hypertrophic astrocytes, whereas Notch1 and Hes5 localized to cells with an immature oligodendrocyte phenotype, and TGF-β1 was associated with perivascular extracellular matrix in the same areas. In contrast, there was negligible Jagged1 expression in remyelinated lesions. Experiments in vitro showed that Jagged1 signaling inhibited process outgrowth from primary human oligodendrocytes. These data are the first to implicate the Notch pathway in the limited remyelination in MS. Thus, Notch may represent a potential target for therapeutic intervention in this disease.

Original languageEnglish (US)
Pages (from-to)1115-1121
Number of pages7
JournalNature Medicine
Volume8
Issue number10
DOIs
StatePublished - Oct 1 2002

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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