title: Notch1 and its ligand Jagged1 are present in remyelination in a T-cell- and antibody-mediated model of inflammatory demyelination.
abstract: The Notch receptor and its ligands are involved in myelination in central nervous system (CNS) development. Re-expression of this pathway in the adult CNS has been proposed to hamper remyelination in multiple sclerosis. Previous studies also revealed that pharmacological inhibition of Notch signaling ameliorates experimental autoimmune encephalomyelitis (EAE). However, in a recent study in toxin-induced demyelination constituents of the Notch signaling pathway were demonstrated in remyelinating lesions indicating that remyelination may occur in the presence of Notch signaling. We examined the expression of Notch1-immunoreactivity (IR) and Jagged1-IR in EAE induced by myelin-oligodendrocyte glycoprotein (MOG). In this model, the combined action of T cells, antibodies and the complement cascade yields a pathology closely reflecting multiple sclerosis. Notch1 and its ligand Jagged1 were differentially expressed in the lesions of MOG-EAE. Notch1-IR on macrophages was highest in actively demyelinating and lowest in remyelinating lesions. The amount of Notch1-positive astrocytes increased during the lesion evolution from demyelination to remyelination. Notch1-positive oligodendrocytes were exclusively present in remyelinating lesions and not found in lesions without signs of remyelination. Astrocytes represented the major source of Jagged1-IR in demyelination and remyelination. In conclusion, our study proves that constituents of the Notch pathway are expressed in remyelination in an animal model of T-cell- and antibody-mediated CNS demyelination. Thus, it is unlikely, at least in the paradigm of MOG-EAE, that Notch signaling is responsible for a failure of remyelination.
authors.affiliation: Department of Neurology, Medical University Graz, Auenbruggerplatz 22, Graz, 8036, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seifert
authors.forename: Jan
authors.initials: J
authors.lastname: Bauer
authors.forename: Robert
authors.initials: R
authors.lastname: Weissert
authors.forename: Franz
authors.initials: F
authors.lastname: Fazekas
authors.forename: Maria K
authors.initials: MK
authors.lastname: Storch
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002452:Cell Count; D002531:Cerebellum / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D051381:Rats; D051881:Receptor, Notch1 / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D036341:Intercellular Signaling Peptides and Proteins; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; C497763:Notch1 protein, rat; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases