The mechanism of the oscillatory gene expression by Hes transcription factors

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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.