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Brain Advance Access published online on August 2, 2004
Brain, doi:10.1093/brain/awh217
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Received February 25, 2004
Revised April 9, 2004
Accepted April 12, 2004

Article

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

Mark F. Stidworthy 1, Stephane Genoud 2, Wen-Wu Li 1, Dino P. Leone 2, Ned Mantei 2, Ueli Suter 2, Robin J. M. Franklin 1*

1 Cambridge Centre for Brain Repair and Centre for Veterinary Sciences, University of Cambridge, UK
2 Institute of Cell Biology, ETH Zürich, Switzerland

* To whom correspondence should be addressed. E-mail: rjf1000{at}cam.ac.uk.


  Abstract

Summary 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 Notch1lox/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.

Keywords: remyelination; notch; jagged; multiple sclerosis; oligodendrocyte.
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