NG2-expressing cells in demyelination and remyelination: studies using new transgenic mouse models

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In this proposal we plan to generate demyelinating lesions using novel transgenic mouse strains. Although early phases of MS and most demyelinating animal models exhibit considerable remyelination, in later phases of the disease remyelination fails leading to irreversible axonal pathology. Remyelination in animal models has been shown to be carried out by surviving mitotic oligodendrocyte progenitor cells (OPC). OPC cells express the NG2 proteoglycan: we have recently generated a transgenic mouse line in which the EYFP gene is inserted in the first exon of the endogeneous NG2 gene, resulting in yellow cells in the CNS when the endogeneous promotor is active thus enabling study of the behaviour of NG2 cells in development as well as in lesions. The lab of Ari Waisman has generated a mouse line in which MOG-expressing oligodendrocytes are deleted after injection of mice with diptheria toxin (MOG-iCre-iDTR mice). In this project we plan to cross these two mouse strains to allow us to induce demyelinating lesions in mice in which NG2–expressing cells are labelled. We will address how NG2+ progenitor cells interact with demyelinated axons, the characteristics of these cells and whether continual cycles of demyelination result in progenitor cell depletion. By generating autoantibodies specific for NG2 via DNA vaccination, we will investigate whether mounting an immune response against the progenitor cells in vivo results in an exacerbation of remyelination due to deletion, or blockage of migration of the OPC. Lastly, we will cross the homozygous NG2- EYFP mice, which are null mutants for NG2 with the MOG-iCreiDTR heterozygous mice, to determine whether the lack of the NG2 protein affects remyelination.