| Budget Amount *help |
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2005: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥11,500,000 (Direct Cost: ¥11,500,000)
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| Research Abstract |
Myelin is a multi-layered membranous lipid insulator surrounding axons that allows the rapid conduction of neuronal impulses. In the central nervous system (CNS), myelin is produced by oligodendrocytes. During development, morphologically immattue oligodendrocyte precursor cells (OPCs) arise from neural stem cells before differentiating into myelinating oligodendrocytes shortly after birth. Fyn tyrosine kinase (Fyn) has been shown to play a central role during OPC differentiation, including inducing morphological changes in the cells and initiating the expression of myelin basic protein (MBP), a major structural protein required for the compaction of myelin sheath. The protein tyrosine phosphatases that are responsible for the positive regulation of Fyn tyrosine kinase activity during this cascade, however, remained unknown. In this reseach project, we found that a protein tyrosine phosphatase, CD45, is involved in this process. Fyn co-immunoprecipitated with CD45 from differentiating
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wild-type OPCs in vitro, while CD45-deficient OPCs failed to differentiate. Additionally, demyelination was observed in CD45-deficient mice in vivo.
Also, from the present study about MS patients' brain, we examined 10 autopsy cases of MS for the expression of FcRγ both in remyelinating areas and demyelinated plaques. The expression of FcRy was confirmed in both OPC/iOligs and microglia in MS lesions. Statistical analysis showed that the density of FcR7-positive OPC/iOligs was approximately 3 times greater in remyelinating areas compared with demyelinated plaques ; the opposite was true of FcRγ-positive microglia. The distribution of FcRγ-negative OPC/iOligs did not differ between the 2 types of lesions. Thus, an increase in FcRγ-positive OPC/iOligs and a decrease in FcRγ-posidve microglia, but not in FcRγ-negative OPC/iOligs, are associated with spontaneous remyelination in MS brains, suggesting a possible role for FcRγ the induction of remyelination.
These results shows that signaling via the gamma chain of immunoglobulin Fc receptors (FcRγ), as well as phosphatation by CD45 phosphatase induces the Fyn-MBP cascade and promotes the morphological differentiation of OPCs. Less
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