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

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.

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Figure 1: Inflammatory cytokines elicit distinct gene expression patterns in human astrocytes: TGF-β1 induces Jagged1 but not Delta1.
Figure 2: Expression of Jagged1, its receptor Notch1, and the downstream effector, Hes5, in acute MS lesions.
Figure 3: Phenotypic identification of cells expressing Jagged1/Notch1/Hes5.
Figure 4: Differential expression of Jagged1 in demyelinating versus remyelinated lesions.
Figure 5: Jagged1 inhibits the maturation of primary human oligodendrocytes in vitro.
Figure 6: Proposed model for activation of the Jagged–Notch–Hes pathway in MS lesions.

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Acknowledgements

We thank K. Weidenheim and B. Poulos for tissue collection; B. Cannella, M.-L. Zhao, W. Shen and H. Knowles for help with immunohistochemistry and cell culture; S. Chen, M. Cotler and J. Fuderanan for microarray construction; L. Li and F.A. McMorris for reagents; and C. Melendez-Vasquez for helpful discussions. We also thank the Albert Einstein Analytical Imaging Facility for assistance with imaging. This study was supported by National Multiple Sclerosis Society Fellowship FG1355 (to G.R.J.) and Grant RG3020 (to B.S.Z.), and USPHS Grants NS40137 (to C.F.B.), NS11920 (to C.F.B. and C.S.R.), NS08952 (to C.S.R.), NS38102 (to B.S.Z.) and MH55477 (to S.C.L.).

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Correspondence to Gareth R. John.

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John, G., Shankar, S., Shafit-Zagardo, B. et al. Multiple sclerosis: Re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med 8, 1115–1121 (2002). https://doi.org/10.1038/nm781

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