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The transcription factor network regulating mammalian neural differentiation

调节哺乳动物神经分化的转录因子网络

基本信息

批准号：
12470025
负责人：
KAGEYAMA Ryoichiro
金额：
$ 7.94万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

Neural development consists of three major steps: (1) maintenance of neural stem cells, (2) neurogenesis and (3) gliogenesis. We elucidated the transcription factors that regulate these steps.A. Maintenance of neural stem cells and gliogenesisHesl and Hes5, mammalian bHLH genes are expressed by neural stem cell and differentiating glia. Cells infected with Hesl- and Hes5-transducing retrovirus remained as neural stem cells or became glia but did not differentiate into neurons. Conversely, in mice mutant for Herl and Hes5, maintenance of neural stem cells was impaired and, as a result, neurons differentiated prematurely, resulting in severe defects of the brain morphogenesis. Thus, Hesl and Hes5 play important roles both in maintenance of neural stem cells and in gliogenesis. We also found that expression of both Hesl mRNA and protein oscillates in a 2-hour periodicity. This oscillation occurs autonomously and depends on the negative feedback of Hesl, which represses its own expression. Thus, Hesl acts as a 2-hour cycle biological clock. Hesl oscillation may be involved in the selection between remaining as stem cells and differentiating into neurons.B. NeurogenesisTwo bHLH genes Mash1 and Math3, are co-expressed by many differentiating neurons. Misexpression of Mash1 and Math3 promoted the neuronal fate determination at the expense of the glial fate. Conversely, in mice double-mutant for Mash1 and Math3, many neurons were missing and, instead, those cells that normally differentiate into neurons adopted the glial fate. These results indicate that Mash1 and Math3 direct neuronal versus glial fate determination. However, bHLH genes alone are not sufficient but combinations with homeobox genes are important for generation of the neuronal diversity.

神经发育包括三个主要步骤：（1）神经干细胞的维持，（2）神经发生和（3）胶质细胞生成。我们阐明了调控这些步骤的转录因子。神经干细胞的维持和胶质细胞的形成Hes1和Hes5，哺乳动物bHLH基因由神经干细胞和分化中的胶质细胞表达。用Hes1和Hes5转导逆转录病毒感染的细胞保持为神经干细胞或成为神经胶质细胞，但不分化为神经元。相反，在Herl和Hes 5突变的小鼠中，神经干细胞的维持受损，因此，神经元过早分化，导致脑形态发生的严重缺陷。因此，Hes1和Hes5在神经干细胞的维持和胶质细胞生成中起重要作用。我们还发现Hesl mRNA和蛋白质的表达都以2小时的周期振荡。这种振荡自主发生，并依赖于抑制其自身表达的Hesl的负反馈。因此，Hesl相当于一个2小时周期的生物钟。Hesl振荡可能参与了干细胞和神经元之间的选择。神经发生两个bHLH基因Mash1和Math3由许多分化的神经元共表达。Mash1和Math3的错误表达促进了神经元的命运决定，代价是胶质细胞的命运。相反，在Mash1和Math3的双突变小鼠中，许多神经元缺失，相反，那些正常分化为神经元的细胞采用了神经胶质的命运。这些结果表明，Mash1和Math3直接神经元与神经胶质细胞的命运决定。然而，单独的bHLH基因是不够的，但与同源框基因的组合是重要的神经元的多样性的产生。