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

一种伴有表观遗传障碍的儿童疾病 -Rett 综合征 - 的调查

• 批准号: 15390330
• 负责人: KUBOTA Takeo
• 金额: $ 9.41万
• 依托单位: University of Yamanashi
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390330/
• 关键词: epigenetics; mental retardation; Rett syndrome; DNA methylation; MeCP2; neuronal cell; glial cell; phosphorylation; 小児疾患; ニューロン; シナプス; ノックアウトマウス; ノック

[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.

[目的]Rett综合征是由MeCP2基因突变引起的一种孤独症。然而，大脑中发生了什么仍有待澄清。该项目的目的是了解当MeCP2蛋白功能不佳时脑细胞的异常。[1st在MeCP2基因敲除小鼠的脑中，在原代神经元细胞中，确认了神经元树突上的棘的形成（与其他发现一起，原稿正在准备中）。[2nd我们发现MeCP 2蛋白不仅在神经元中表达，而且在神经胶质细胞中表达。我们还发现MeCP 2功能障碍导致神经胶质细胞的生长迟缓，这表明Rett综合征患者中所见的小头畸形可能与早期发育期间神经胶质细胞的生长迟缓有关（永井et al.，Dev Brain Res 2005）。[3rd我们鉴定了MeCP2蛋白不仅在神经元细胞的细胞核中表达，而且在细胞质中表达，并且细胞质MeCP2被磷酸化，而核MeCP2没有，这表明MeCP2从细胞质中的转运可能与磷酸化有关（Mandelipt提交）。[进一步实验]本项目的研究结果将有助于对Rett综合征及其他自闭症疾病发病机制的理解。

项目成果

Myelination state of a fetal case of Pelizaeus-Merzbacher disease : Immunopathological considerations.

Pelizaeus-Merzbacher 病胎儿病例的髓鞘形成状态：免疫病理学考虑。

• 发表时间: 2003
• 期刊: Annal Neurol 54
• 作者: Shiraishi K;Itoh M;Sano K;Takashima Y;Kubota T.
• 通讯作者: Kubota T.

Granulocyte-macrophage colony-stimulating factor induces de novo methylation of the p15 CpG island in hematopietic cells.

粒细胞巨噬细胞集落刺激因子诱导造血细胞中 p15 CpG 岛的从头甲基化。

• 发表时间: 2005
• 期刊: Cytokine 31・3
• 作者: Zhao XY;et al.
• 通讯作者: et al.

久保田健夫: "加齢・疾患とエピジェネティックス「神経疾患とエピジェネティックス」"現代医療. 35・5. 122-128 (2003)

久保田武夫：“衰老/疾病和表观遗传学‘神经疾病和表观遗传学’”现代医学35・5。

A transcriptional represser MeCP2 causing Rett syndrome is expressed in embryonic non-neuronal cells and controls their growth.

导致 Rett 综合征的转录抑制因子 MeCP2 在胚胎非神经元细胞中表达并控制其生长。

• 发表时间: 2005
• 期刊: Brain Res Dev Brain Res 157・1
• 作者: Nagai K;et al.
• 通讯作者: et al.

Matsumura et al.: "Severe Prader-Willi syndrome with a large deletion of chromosome 15 due to an unbalanced t(15;22)(q14;11.2) translocation."Clinical Genet. 63・1. 79-81 (2003)

Matsumura 等人：“由于不平衡 t(15;22)(q14;11.2) 易位导致 15 号染色体大量缺失的严重 Prader-Willi 综合征。”Clinical Genet 63・1 (2003)。