The aims of this proposal are twofold: (1) to study the origin and differentiation of neuroglia in the central nervous system (CNS) and (2) to determine the underlying cause of the myelin deficiency in a mutant mouse known as jimpy. A combination of morphologic, autoradiographic, immunocytochemical and biochemical methods will be used. The lineage of astrocytes and oligodendrocytes in normal animals will be traced immunocytochemically using cell specific markers for astrocytes (glial fibrillary acidic protein, S-100 and an anti-astrocytic monoclonal), oligodendrocytes (carbonic anhydrase II) and myelin (myelin basic protein, proteolipid protein and galactocerebroside). Immunocytochemistry using these glial specific and myelin-enriched markers will be combined with thymidine autoradiography to determine whether the dividing glial cells which appear to be in the early stages of differentiation have already synthesized glial and myelin-enriched components. In jimpy mice, the oligodendrocytes undergo increased proliferation and premature death (Skoff, '82), factors which probably contribute to the hypomyelination. The basis for these changes will be investigated by studying the life span of these cells, the length of their cell cycle, their capacity to form myelin and the number of oligodendrocytes available for myelination. The effects of hormones upon gliogenesis and myelinogenesis have been well documented from a biochemical standpoint but poorly described from a morphologic perspective. Experimental hypo- and hyperthyroidism will be produced and their effects upon the structure of the myelin sheath and glia in normal mice will be studied and compared to jimpys. Our interest in hormones stems from our recent demonstration that the thyroid gland of the jimpy mouse is morphologically abnormal. Serum levels of thyroxine and thyroglobulin will be assayed to determine if a physiologic component exists. The glandular abnormality and other information suggests that a metabolic defect, possibly in respiratory metabolism, may be the underlying cause of the hypomyelination. In support of this hypothesis, our preliminary observations of astrocytes in jimpy suggest increases in glycogen and gliosis in normally non-myelinated regions. Verification of these observations and completion of the studies described above should provide a better understanding of the ontogeny of glia and the factors which regulate their differentiation.
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