Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination

Yueting Zhang, Azeb Tadesse Argaw, Blake T. Gurfein, Andleeb Zameer, Brian J. Snyder, Changhui Ge, Q. Richard Lu, David H. Rowitch, Cedric S. Raine, Celia F. Brosnan, Gareth R. John

Research output: Contribution to journalArticle

134 Scopus citations

Abstract

In the developing CNS, Notch1 and its ligand, Jagged1, regulate oligodendrocyte differentiation and myelin formation, but their role in repair of demyelinating lesions in diseases such as multiple sclerosis remains unresolved. To address this question, we generated a mouse model in which we targeted Notch1 inactivation to oligodendrocyte progenitor cells (OPCs) using Olig1Cre and a floxed Notch1 allele, Notch112f. During CNS development, OPC differentiation was potentiated in Olig1Cre:Notch1 12f/12f mice. Importantly, in adults, remyelination of demyelinating lesions was also accelerated, at the expense of proliferation within the progenitor population. Experiments in vitro confirmed that Notch1 signaling was permissive for OPC expansion but inhibited differentiation and myelin formation. These studies also revealed that astrocytes exposed to TGF-β1 restricted OPC maturation via Jagged1-Notch1 signaling. These data suggest that Notch1 signaling is one of the mechanisms regulating OPC differentiation during CNS remyelination. Thus, Notch1 may represent a potential therapeutical avenue for lesion repair in demyelinating disease.

Original languageEnglish (US)
Pages (from-to)19162-19167
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number45
DOIs
StatePublished - Nov 10 2009

Keywords

  • Autoimmunity
  • CNS repair
  • Multiple sclerosis
  • Myelin
  • Oligodendrocyte progenitor

ASJC Scopus subject areas

  • General

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    Zhang, Y., Argaw, A. T., Gurfein, B. T., Zameer, A., Snyder, B. J., Ge, C., Lu, Q. R., Rowitch, D. H., Raine, C. S., Brosnan, C. F., & John, G. R. (2009). Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination. Proceedings of the National Academy of Sciences of the United States of America, 106(45), 19162-19167. https://doi.org/10.1073/pnas.0902834106