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Elucidating the mechanism of myelination : FcRγ-Fyn-MBP stream is critical for the CNS myelination.

阐明髓鞘形成机制：FcRγ-Fyn-MBP 流对于中枢神经系统髓鞘形成至关重要。

基本信息

批准号：
16300124
负责人：
ASOU Hiroaki
金额：
$ 4.74万
依托单位：
Tokyo Metropolitan Foundation for Research on Aging and Promotion of Human Welfare
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Elucidation of the mechanism of CNS myelinogenesis is ultimately required to cure demyelinating disease. We have elucidated the mechanism whereby the γ chain of immunoglobulin Fc recepter(FcR γ ), an essential signaling molecule of the immune system, functions as a trigger for oligodendroglial myelinogenesis. FcR γ signaling results in the up-regulation of Fyn tyrosine kinase (Fyn) and myelin basic protein (MBP) expression levels, in addition to the morphological differentiation of oligodendroglia. Mice deficient in FcR γ demonstrate severely disturbed myelinogenesis, similar to the defect observed in mice deficient in either Fyn or MBP. FcR γ -Fyn double deficient mice exhibit severer hypomyelination and decrease in MBP than those of both single mutant mice, implying that FcR γ -Fyn-MBP cascade is indeed critical for the myelinogenesis. We have also detected expression of Fc recepters specific for immunoglobulin G in conjunction with FcR γ in oligodendroglia, suggesting immunogloblins may contribute to myelinogenesis. Expression of CD45, a regulator of Fyn, in oligodendroglia suggests the involvement of this molecule in the proposed mechanism. Our findings uncover a new connection between the brain and the immune system involved in myelinogenesis, introducing a novel therapeutic avenue leading to a possible cure for demyelinating disease.

最终需要阐明中枢神经系统髓鞘生成的机制才能治愈脱髓鞘疾病。我们已经阐明了免疫球蛋白Fc受体γ链(FcRγ)是免疫系统的重要信号分子，作为少突胶质细胞髓鞘生成的触发因子的机制。FCRγ信号导致Fyn酪氨酸激酶和髓鞘碱性蛋白的表达水平上调，并导致少突胶质细胞的形态分化。缺乏FCRMBP的小鼠表现出严重的髓鞘生成障碍，类似于缺乏FYN或γ的小鼠的缺陷。FcRγ-FYN双缺陷小鼠表现出比这两个单突变小鼠更严重的髓鞘抑制和血压下降，这表明FcRγ-FYN-MBp级联确实在髓鞘形成中起关键作用。我们还检测到免疫球蛋白G的Fc受体和FcRγ在少突胶质细胞中的表达，提示免疫球蛋白可能有助于髓鞘的形成。Fyn的调节者CD45在少突胶质细胞中的表达表明该分子参与了所提出的机制。我们的发现揭示了参与髓鞘生成的大脑和免疫系统之间的新联系，引入了一种新的治疗途径，可能治愈脱髓鞘疾病。