We have shown that the earliest precursors for oligodendrocytes (the myelinating cells of the CNS) arise in the ventral ventricular region of the spinal cord at a particular time in development. The proposed studies will identify the cellular and molecular regulators of oligodendrocyte induction and define the guidance cues that control the directional migration of oligodendrocyte precursors. The ventral origin of oligodendrocytes depends on local environmental signals that include sonic hedgehog (Shh) and neuregulin (NRG). When oligodendrocyte precursors first arise in development, the ventral spinal cord is populated by motor neurons and long axon tracts, and our recent studies suggests that cues from these cells are required to induce oligodendrocytes. Our working hypothesis is that Shh and NRG must be expressed by neurons or their processes in order to generate oligodendrocyte precursors. In the first aim we will determine whether spinal cord oligodendrocytes can be induced by neuronal and/or axonal signals using retina as a source of neurons that lacks oligodendrocytes. We will then determine if neuronal induction is dependent on Shh and NRG and whether NRG and Shh have to be made by the same neuronal cell. In the second aim we will test the hypothesis that optic nerve oligodendrocytes are induced by signals from retinal axons and determine whether transplanted retina can induce oligodendrocytes in dorsal spinal cord. Although they arise in restricted locations, oligodendrocytes are widely distributed in the adult CNS. Thus the precursors must migrate through the CNS in order to myelinate axonal tracts. We will test the hypothesis that netrin, made by ventral midline cells, acts as a repulsive cue to guide the migration of oligodendrocyte precursors to presumptive white matter. In the third aim we will examine the expression of netrin-1 in the developing spinal cord, and use in vitro migration assays to show the chemorepellant function of netrin and identify functional netrin receptors on oligodendrocyte precursors. In addition, we will determine whether repulsive molecules such as slit guide oligodendrocyte precursor migration. In the forth aim we will compare the distribution of oligodendrocyte precursors in the optic system and spinal cord of wild type and netrin knockout animals to determine whether the migration of these cells is perturbed in the absence of netrin. These studies will provide important new information on the mechanisms underlying oligodendrocyte development in the vertebrate CNS, and will lead to novel approaches to achieve remvelination after CNS injury or demyelinating diseases.
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