The transcription factor network regulating mammalian neural differentiation

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；(3)神经胶质形成。我们阐明了调控这些步骤的转录因子。a.神经干细胞和胶质形成的维持Hes1和Hes5，哺乳动物的bHLH基因由神经干细胞和分化的胶质细胞表达。感染了转导Hes1和Hes5逆转录病毒的细胞仍然是神经干细胞，或者成为神经胶质细胞，但不能分化为神经元。相反，在HERL和Hes5突变的小鼠中，神经干细胞的维持受到损害，结果是神经元过早分化，导致大脑形态发生严重缺陷。因此，Hes1和Hes5在神经干细胞的维持和神经胶质形成中都起着重要的作用。我们还发现，Hesl mRNA和蛋白的表达都以2小时为周期振荡。这种振荡是自主发生的，依赖于Hesl的负反馈，而Hesl抑制了它自己的表达。因此，Hesl就像一个2小时周期的生物钟。B.神经发生bHLH基因Mash1和Math3在许多分化的神经元中共表达。Mash1和Math3的错误表达以牺牲神经胶质细胞命运为代价，促进了神经元命运的决定。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直接决定神经元和神经胶质细胞的命运。然而，仅有bHLH基因是不够的，但与同源框基因的组合对于神经元多样性的产生是重要的。

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.