Investigation of A Child Disease with Epigenetic Disorder -Rett Syndrome-

[目的]Rett综合征是一种由MeCP2基因突变引起的自闭症疾病。然而，大脑中发生了什么仍有待澄清。这个项目的目的是了解当MeCP2蛋白功能不佳时脑细胞的异常。[1财政年度]我们发现来自MeCP2基因敲除小鼠大脑的初级神经元细胞中神经元树突上的棘突形成(连同其他发现，手稿正在准备中)。[2财政年度]我们发现MeCP2蛋白不仅在神经元中表达，而且在神经胶质细胞中也表达。我们还发现MeCP2功能障碍导致神经胶质细胞生长迟缓，提示在Rett综合征患者中出现的小头畸形可能与早期发育过程中神经胶质细胞的生长迟缓有关(Nagai等人，Dev Brain RES 2005)。[3财政年度]我们发现MeCP2蛋白不仅在神经元细胞的胞核和胞浆中表达，而且胞浆中的MeCP2被磷酸化，而细胞核中的MeCP2不表达，这表明MeCP2从胞浆中的运输可能与磷酸化有关(提交的手稿)。[进一步的实验]该项目的发现将有助于理解Rett综合征和其他自闭症疾病的发病机制。

[Aim]Rett syndrome is an autistic disease caused by MeCP2 gene mutations. However, what happened in the brain is remained to be clarified. The aim of this project to know abnormalities in the brain cells when MeCP2 protein do not function well.[1st fiscal year]We identified that spine formation on dendrites of neurons in primary neuronal cells derived from the brain of MeCP2 knock-out mouse (together with other findings, the manuscript is in preparation).[2nd fiscal year]We identified that MeCP2 protein is expressed in not only in neurons but also in glial cells. We also found that MeCP2 malfunction results in growth retardation of glial cells, suggesting that microcephaly seen in Rett syndrome patients may be related to the growth retardation of glial cells during early development (Nagai et al., Dev Brain Res 2005).[3rd fiscal year]We identified that MeCP2 protein is expressed in not only in the nucleus but also cytosol of a neuronal cell, and that cytosolic MeCP2 is phosphorylated whereas nucleic MeCP2 is not, suggesting that transport of MeCP2 from cytosol may be associated with phosphorylation (Manuscript submitted).[Further experiment]The findings in this project will contribute to the understanding of pathogenesis of Rett syndrome and other autistic diseases.