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

1)NE-DLG是果蝇DLG的人类同源物。我们发现NE-DLG在神经元的突触膜部位与NMDA受体亚单位2B结合，并且它们的表达随着突触发生的开始而增加。NE-DLG被发现在钙调素和钙的存在下与PSD-95相互作用，并被推测调节NMDA受体的聚集以形成突触。此外，我们还鉴定了一种新的胞质NE-DLG相互作用蛋白，命名为p51-nedasin。我们发现奈达辛竞争性地抑制NMDA受体与NE-DLG的结合。这些结果表明，nedasin改变了神经细胞发育过程中突触部位DLG相关的分子聚集。2)致死性(3)恶性脑瘤(D-1(3)MBT)基因的隐性突变导致果蝇幼虫脑神经母细胞恶性增殖。D-1(3)MBT蛋白与PcG蛋白中的SCM蛋白结构相似。我们分离了1(3)MBT基因的人类同源基因，命名为h-1(3)MBT。H-1(3)MBT在大多数人类正常组织和培养细胞系中都有表达。H-1(3)MBT蛋白在有丝分裂细胞中呈点状和散在分布，定位于浓缩的染色体上。通过CRE介导的基因激活系统过表达h-1(3)MBT会导致染色体分离和胞质分裂失败，从而导致U251 MG细胞形成多核。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，可能在细胞分裂的正常进行中发挥作用。

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.