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Studies on generation and differentiation of central neurons in association with postmitotic mechanisms

中枢神经元的产生和分化与有丝分裂后机制的研究

基本信息

批准号：
10480217
负责人：
YOSHIKAWA Kazuaki
金额：
$ 6.21万
依托单位：
Osaka 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

项目摘要

Neurons in the central nervous system withdraw from the cell cycle in an irreversible manner after their differentiation from neural stem cells and never proliferate throughout their lifetimes. The permanent mitotic arrest is the most fundamental phenotype displayed by differentiated neurons. The present study focused on the effects of necdin, a neural differentiation-specific protein, and its interactions with the cell cycle regulatory proteins E2F and p53. The research results are as follows. [1] Necdin bound to the transcription factor E2F1 and suppressed transcription of various genes involved in DNA replication. [2] Necdin bound to the transactivation domain of p53 and suppresses p53-dependent transcriptional activity. In addition, necdin suppressed p53-induced apoptosis. [3] Necdin functioned as a transcription factor that binds to specific DNA sequences. [4] The human necdin gene is localized in chromosome 15q11-q12, which is the region responsible for the pathogenesis of the Prader-Willi syndrome, a genome imprinting-associated neurogenic disorder. Necdin was expressed only from the paternal allele as determined using necdin gene knockout mice. [5] E2F1 mRNA was expressed in postmitotic neurons, and the E2F1 protein was degraded in the proteasome. [6] Postmitotic neurons underwent apoptosis when E2F1 was overexpressed. [7] The above findings suggest that necdin interacts with cell cycle regulatory factors E2F1 and p53 and plays an important role in terminally differentiation and maintenance of differentiation phenotypes.

中枢神经系统神经元从神经干细胞分化后，以不可逆的方式退出细胞周期，终生不增殖。永久性有丝分裂阻滞是分化神经元最基本的表型。本研究的重点是神经分化特异性蛋白necdin的作用及其与细胞周期调节蛋白E2F和p53的相互作用。研究结果如下：Necdin与转录因子E2F1结合，抑制参与DNA复制的各种基因的转录。Necdin结合到p53的反活化结构域并抑制p53依赖的转录活性。此外，necdin抑制p53诱导的细胞凋亡。Necdin是一种结合特定DNA序列的转录因子。人类necdin基因位于染色体15q11-q12上，该区域与Prader-Willi综合征（一种与基因组印记相关的神经源性疾病）的发病机制有关。用Necdin基因敲除小鼠测定，Necdin仅从父系等位基因中表达。[5] E2F1 mRNA在有丝分裂后神经元中表达，E2F1蛋白在蛋白酶体中降解。当E2F1过表达时，有丝分裂后神经元发生凋亡。以上研究结果表明，necdin与细胞周期调节因子E2F1和p53相互作用，在终末分化和维持分化表型中发挥重要作用。