Notch1 and Jagged1 are expressed after CNS demyelination, but are not a major rate-determining factor during remyelination

Brain. 2004 Sep;127(Pt 9):1928-41. doi: 10.1093/brain/awh217. Epub 2004 Aug 2.

Abstract

The reasons for the eventual failure of repair mechanisms in multiple sclerosis are unknown. The presence of precursor and immature oligodendrocytes in some non-repairing lesions suggests a mechanism in which these cells either receive insufficient differentiation signals or are exposed to differentiation inhibitors. Jagged signalling via Notch receptors on oligodendrocyte precursor cells (OPCs) inhibits their differentiation during development and the finding that both notch and jagged are expressed in multiple sclerosis lesions has fostered the view that this signalling pathway may explain remyelination failure. In this study, we show that Notch1 is expressed on adult OPCs and that there are multiple cellular sources of its ligand Jagged1 in a rodent model of remyelination. However, despite their expression, the lesions undergo complete remyelination. To establish whether Notch-jagged signalling regulates the rate of remyelination we compared their expression profiles in young animals with those in older animals, where remyelination occurs more slowly, but could find no correlation between expression and remyelination rate. Finally we found that OPC-targeted Notch1 ablation in cuprizone-treated Plp-creER Notch1(lox/lox) transgenic mice yielded no significant differences in remyelination parameters between knock-out and control mice. Thus, in contrast to developmental myelination, adult expression of Notch1 and Jagged1 neither prevents nor plays a major rate-determining role in remyelination. More generally, the re-expression of developmentally expressed genes following injury in the adult does not per se imply similar function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / immunology
  • Animals
  • Astrocytes / immunology
  • Axons / immunology
  • Brain / immunology*
  • Calcium-Binding Proteins
  • Cerebellum / immunology
  • Female
  • Gene Expression / genetics
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Jagged-1 Protein
  • Lac Operon / genetics
  • Macrophages / immunology
  • Membrane Proteins / analysis
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / metabolism
  • Myelin Sheath / physiology
  • Oligodendroglia / immunology*
  • Oligodendroglia / metabolism
  • RNA, Messenger / immunology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Notch1
  • Receptors, Cell Surface / analysis
  • Receptors, Cell Surface / immunology
  • Receptors, Cell Surface / metabolism*
  • Rhombencephalon / immunology
  • Schwann Cells / immunology
  • Serrate-Jagged Proteins
  • Stem Cells / immunology
  • Stem Cells / metabolism
  • Transcription Factors / analysis
  • Transcription Factors / immunology
  • Transcription Factors / metabolism*
  • Trigeminal Ganglion / immunology

Substances

  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Jag1 protein, mouse
  • Jag1 protein, rat
  • Jagged-1 Protein
  • Membrane Proteins
  • Notch1 protein, mouse
  • Notch1 protein, rat
  • RNA, Messenger
  • Receptor, Notch1
  • Receptors, Cell Surface
  • Serrate-Jagged Proteins
  • Transcription Factors
  • delta protein