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Identification of the novel genes which regulated differentiation of neuronal tissues and the diseases caused by their defects

调控神经组织分化的新基因及其缺陷引起的疾病的鉴定

基本信息

批准号：
10470296
负责人：
SAYA Hideyuki
金额：
$ 8.13万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470296/
关键词：
Drosophila NE-dlg p51-nedasin 1(3)mbt synapse calmodulin EST Polycomb DLG NMDAレセプター PDZドメイン p51-nedasin P-dlg

项目摘要

1) NE-dlg is a human homologue of the Drosophila DLG. We found that NE-dlg binds to NMDA receptor subunit 2B at the synaptic membrane sites in neurons, and that their expressions increase in parallel with the onset of a synaptogenesis. NE-dlg was found to interact with PSD-95 in the presence of calmodulin and calcium and is speculated to regulate the clustering of NMDA receptors to form the synapses. Furthermore, we identified a novel cytoplasmic NE-dlg-interacting protein, termed p51-nedasin. We found that nedasin competitively inhibits the binding between the NMDA receptors and NE-dlg. These results suggest that nedasin modifies the dlg-related molecular clustering at the synaptic sites during development of neuronal cells.2) Recessive mutations of the lethal (3)malignant brain tumor (D-1(3)mbt) gene result in malignant proliferation of the neuroblasts in the Drosophila larval brain. The structure of D-1(3)mbt protein is similar to sex comb on midleg (Scm) protein which is a member of Polycomb group (PcG) proteins. We isolated a human homolog of the 1(3)mbt gene, designated h-1(3)mbt. The h-1(3)mbt is expressed in most of the human normal tissues and cultured cell lines. The h-1(3)mbt protein shows a speckled and scattered distribution in interphase nuclei and localizes to condensed chromosomes in mitotic cells. Overexpression of h-1(3)mbt by a Cre-mediated gene activation system leads to failures of proper chromosome segregation and cytokinesis, which result in formation of multinuclei in U251MG cells. These observations suggest that h-1(3)mbt protein has functions distinct from those of PcG proteins and may play a role in proper progression of cell division.

1)NE-dlg是果蝇DLG的人类同源物。我们发现NE-dlg在神经元的突触膜位点与NMDA受体亚基2B结合，并且它们的表达随着突触发生的开始而平行增加。发现NE-dlg在钙调蛋白和钙的存在下与PSD-95相互作用，并推测其调节NMDA受体的聚集以形成突触。此外，我们确定了一种新的细胞质NE-dlg相互作用蛋白，称为p51-nedasin。我们发现，nedasin竞争性抑制NMDA受体和NE-dlg之间的结合。这些结果表明nedasin改变了神经元发育过程中突触部位dlg相关分子的聚集。2）致死性恶性脑肿瘤（D-1（3）mbt）基因的隐性突变导致果蝇幼虫脑中神经母细胞的恶性增殖。D-1（3）mbt蛋白的结构与多梳组（Polycomb group，PcG）中的性梳（Sex comb on midleg，Scm）蛋白相似。我们分离了一个人类1（3）mbt基因的同源物，命名为h-1（3）mbt。h-1（3）mbt在人体正常组织和培养细胞系中均有表达。h-1（3）mbt蛋白在间期核中呈斑点状和散在分布，在有丝分裂细胞中定位于浓缩的染色体。Cre介导的基因激活系统使h-1（3）mbt过表达，导致U251 MG细胞染色体分离和胞质分裂失败，形成多核。这些观察结果表明，h-1（3）mbt蛋白具有不同于PcG蛋白的功能，并可能在细胞分裂的正常进程中发挥作用。