Multiple Sclerosis (MS) is a paralyzing disease affecting young adults. While a number of experimental drugs are available to minimize the devastation of the disease's course the cause of MS is unknown. A central issue for the treatment of MS is whether oligodendrocytes or resident oligodendrocyte precursors have the potential to remyelinate axons following episodes of demyelination. We have identified a novel variant of human high molecular weight (HMW) microtubule-associated protein-2, designated MAP-2+13, and have generated monoclonal antibodies specific to this splice form. Immunocytochemistry with light and electron microcopy have demonstrated MAP-2+13 staining in human fetal oligodendrocytes during process extension and active myelination, and in numerous oligodendrocytes adjacent to a zone of demyelination in sections from MS lesions. MAP-2+13 is either minimally or not expressed in oligodendrocytes in the normal adult CNS. The hypothesis to best tested in this proposal is that MAP-2+13 is required for the elaboration of oligodendrocyte processes during myelination and that it can be used as a marker for myelinating and remyelinating oligodendrocytes. To determine whether MAP-2+13 expression parallels myelination within the developing CNS, a range of fetal ages will be examined by double-label immunofluorescence and Confocal microscopy, immunoblotting and electron microscopy. MAP-2+13 expression in MS lesions will be extensively examined to determine if the expression correlates with remyelination. Studies will correlate MAP-2+13 expression with the type of lesion and will be compared with age-matched, non neurologic sections. Rat progenitor cells and primary oligodendrocyte cultures will permit the study of MAP-2+13 in a well characterized in vitro system. Analysis will include how changes in MAP-2+13 expression correlate with process outgrowth and oligodendrocyte maturation. These studies permit the examination of a newly identified MAP-2 form in oligodendrocytes and the potential to gain insight into the extension of processes during myelination and disease. Attempts to identify developmentally regulated genes and to understand the regulation involved in the extension of myelinating processes is beneficial for both our understanding of normal CNS development and for treating demyelinating diseases such as Multiple Sclerosis.
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