Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation.
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-beta 1 (TGF-beta 1), 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-beta 1 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.
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000473:pathology / Q000503:physiopathology*; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000378:metabolism*; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D011506:Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072099:Serrate-Jagged Proteins; C508960:TGFB1 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1