The mechanism of the oscillatory gene expression by Hes transcription factors

在胚胎发育中，许多生物事件在严格的时间安排下顺序发生。然而，生物钟的作用机制仍有待阐明。在小鼠的体细胞发生过程中，每隔2小时就会有一对体节从卵裂期前的中胚层中萌发出来，这表明体节的分割是由一个2小时周期的生物钟控制的。在本研究中，我们揭示了生物钟具有2小时周期的分子机制。在卵裂期前的中胚层中，包括编码负转录因子的Hes7在内的几个基因表现出与体节分割相对应的周期性表达。在此之前，我们已经证明了Hes7对于体细胞发生和周期基因表达都是必不可少的。在这项研究中，我们发现Hes7蛋白周期性地抑制周期基因的启动子，并建立一个负反馈环作为生物时钟的主要机制，周期为2小时。此外，我们还产生了具有较长半衰期的Hes7突变小鼠，并证明了Hes7蛋白的不稳定对于基因表达的持续振荡至关重要。因此，控制周期性体节分割的生物时钟依赖于Hes7的负反馈回路和Hes7蛋白在成熟前中胚层细胞中的快速降解。

In embryogenesis, many biological events sequentially occur in a strict time schedule. However, the mechanism of biological clocks remains to be elucidated. During mouse somitogenesis, a pair of somites buds off from the presomitic mesoderm every 2 hours, suggesting that somite segmentation is controlled by a biological clock with 2-hour cycle. In this study, we revealed the molecular mechanism of the biological clock with 2-hour cycle.In the presomitic mesoderm, several genes including Hes7, which encodes a negative transcription factor, display cyclical expression corresponding to the somite segmentation. Previously, we showed that Hes7 is essential for both somiotogenesis and cyclical gene expression. In this study, we showed that Hes7 protein periodically represses the promoters of the cyclical genes and establishes a negative feedback loop as a major mechanism of the biological clock with 2-hour cycle. Moreover, we generated the mutant mice that have Hes7 with a longer half-life, and demonstrated that instability of Hes7 protein is crucial for sustained oscillation of gene expression. Thus, the biological clock that controls periodic somite segmentation depens on the negative feedback loop of Hes7 and rapid degradation of Hes7 protein in the presomitic mesoderm cells.