Remyelination, the process by which new myelin sheaths are restored to demyelinated axons, is an unusual example of a regenerative process in the adult mammalian CNS, and is mediated by newly generated oligodendrocytes. These cells are derived from precurs or cells. However, two issues remain unresolved: 1) which precursor cells give rise to oligodendrocytes, and 2) are these cells multi-potent following demyelination, giving rise to cell types other than oligodendrocytes? To address these issues this project will use cre-lox technology in which stage specific promoters will be used to express an inducible Cre (Cre-ER) and thereby activate expression of marker genes. This will enable identification of precursor cells and the cells into which they differentiate following CNS demyelination.
We will use mice in which Cre is expressed using the promoter for PDGFRa, a gene exclusively expressed by oligodendrocyte precursor cells in adult white matter. Since remyelinating cells may come from other populations of precursors that do not express PDGFRa, we will also use mice in which Cre expression is controlled by PLP, a gene expressed more widely by cells of the oligodendrocyte lineage. Both these mice are available to the host laboratory. Focal areas of demyelination will be created in spinal cord white matter by injection of lysolecithin or in corpus callosum by dietary administration of cuprizone. The identity of marker gene expressing cells occurring in response to demyelination and will be established by immunocyto chemistry or in situ hybridisation for oligodendrocytes, astrocytes, Schwann cells and neurons.
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