The extent to which Schwann cells can migrate in the central nervous system and methods by which this """"""""abnormal"""""""" microenvironment can be manipulated to foster the axonal-glial cell interactions required by myelination, are to be investigated. In this proposal, two hypomyelinating mutants, the shaking pup and the myelin deficient rat will be used to examine the potential for Schwann cell invasion, proliferation and myelination of central nervous system axons, and the glial interactions which both underlie and are required for this reparative process. The approaches to be used are: 1) Promote Schwann cell invasion of the spinal cord using (a) irradiation, (b) grafted peripheral nerve, or cultured Schwann cells, and (c) the injection of myelin/glial toxic chemicals; these are all known to cause central nervous system Schwann cell invasion; 2) Use qualitative and quantitative light and electron microscopy and autoradiographic techniques to evaluate glial cells, myelin volume and glial cell interactions in the early neonatal mutants and in older animals which have had their lifespan lengthened by hand rearing techniques; 3) Use the carrier females of both traits (heterozygotes) to examine the focal myelin deficits in the optic nerve and spinal cord of these animals. Study of the interactions between adjacent clones of glial cells and axons of different genotypes in these mosaic patches will provide basic information on the cell interactions which occur when these cells develop together in a non-manipulated environment. These results will have importance to neurobiology and to human demyelinating diseases, especially Multiple Sclerosis, where the paucity of remyelination remains a major unsolved problem. The presence of a population of persistently non-myelinated axons in an astrocytic matrix in the shaking pup and myelin deficient rat, mimics the microscopic appearance of the MS plaque. Thus, these mutants provide the opportunity to experimentally manipulate these cellular interactions and study the feasibility of Schwann cell invasion and myelination of CNS axons. Therefore, the proposed experiments are likely to shed new light on the rules which govern the functioning of Schwann cells within the confines of the central nervous system.
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