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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS015338-09
Application #
3396162
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1978-09-01
Project End
1987-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
9
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Wayne State University
Department
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Skoff, R P; Ghandour, M S; Knapp, P E (1994) Postmitotic oligodendrocytes generated during postnatal cerebral development are derived from proliferation of immature oligodendrocytes. Glia 12:12-23
Knapp, P E; Booth, C S; Skoff, R P (1993) The pH of jimpy glia is increased: intracellular measurements using fluorescent laser cytometry. Int J Dev Neurosci 11:215-26
Knapp, P E; Skoff, R P; Booth, C S (1993) Essential prerequisites for remyelination of oligodendrocytes. Division, motility, and structural rearrangement. Adv Neurol 59:105-12
Knapp, P E; Skoff, R P (1993) Jimpy mutation affects astrocytes: lengthening of the cell cycle in vitro. Dev Neurosci 15:31-6
Knapp, P E (1992) The cell cycle of glial cells grown in vitro: an immunocytochemical method of analysis. J Histochem Cytochem 40:1405-11
Ghandour, M S; Skoff, R P (1991) Double-labeling in situ hybridization analysis of mRNAs for carbonic anhydrase II and myelin basic protein: expression in developing cultured glial cells. Glia 4:1-10
Knapp, P E; Skoff, R P (1991) Expression of myelin glycolipids and proteins in mitotic and postmitotic murine oligodendrocytes. Ann N Y Acad Sci 633:508-10
Skoff, R P; Knapp, P E (1991) Division of astroblasts and oligodendroblasts in postnatal rodent brain: evidence for separate astrocyte and oligodendrocyte lineages. Glia 4:165-74
Skoff, R P; Knapp, P E (1991) Lineage and differentiation of oligodendrocytes in the brain. Ann N Y Acad Sci 633:48-55
Knapp, P E (1991) Studies of glial lineage and proliferation in vitro using an early marker for committed oligodendrocytes. J Neurosci Res 30:336-45

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