Myelination is a crucial process in vertebrate CNS maturation. Lack of myelination during development or loss of myelin in the adult leads to severe functional deficits. CNS myelin is produced by oligodendrocytes that develop in appropriate numbers and at appropriate locations to myelinate all long projection axons. The local control of oligodendrogenesis during development or following demyelinating diseases is not well understood. We recently identified a novel regulatory mechanism that appears to play a key role in regulating the development of oligodendrocytes and in myelination. The chemokine GRO-alpha, signaling through its receptor, CXCR2, regulates the proliferation of oligodendrocyte precursors in response to platelet derived growth factor (PDGF) and provides a potent stop-signal for oligodendrocyte precursor migration. In this renewal application we will use transgenic animals that either lack CXCR2 receptors, or overexpress the ligand GRO-alpha to define the function of GRO-alpha/CXCR2 signaling during oligodendrocyte development and in response to demyelination. To unambiguously identify oligodendrocyte lineage cells we will utilize transgenic animals in which these cells are specifically labeled through expression of Enhanced Green Fluorescent Protein (EGFP) driven off the PLP promoter. We will 1) test if the GRO-alpha/CCR2 pathway regulates development of oligodendrocytes and myelination in the spinal cord, by comparing the timing and degree of myelination between normal and CXCR2 null animals; 2) identify if GRO-aplha/CXCR2 signaling inhibits the migration and dispersal of oligodendrocyte precursors by transplanting EGFP+ cells into different environments as well as direct time lapse migration analyses of EGFP-labeled cells in slice preparations; 3) determine whether GRO-alpha/CXCR2 signaling enhances or inhibits remyelination in the adult CNS by comparing recovery from lysolecithin induced demyelination or induction of EAE in wild type and CXCR2-null animals. These studies will define GRO-alpha as an important regulatory molecule in oligodendrogenesis and a potential target for therapy in diseases of myelin, such as Multiple Sclerosis, and disorders of unregulated gliogenesis such as oligodendroglioma
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