The mechanism of the oscillatory gene expression by Hes transcription factors

Hes转录因子振荡基因表达的机制

• 批准号: 15570176
• 负责人: BESSHO Yasumasa
• 金额: $ 2.37万
• 依托单位: Nara Institute of Science and Technology (2004)Kyoto University (2003)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15570176/
• 关键词: Developmental Biology; Biological clock; Transcription factor; Mouse; Somite; Segmentation; 発生; 分子時計; ユビキチン化; ネガディブフィードバック

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.

在胚胎发生过程中，许多生物事件按照严格的时间表顺序发生。然而，生物钟的作用机制仍有待阐明。在小鼠体细胞发生过程中，每2小时就有一对体裂体从体前中胚层脱落，这表明体裂体的分裂受生物钟控制，以2小时为周期。在这项研究中，我们揭示了2小时周期生物钟的分子机制。在体前中胚层中，包括Hes7在内的一些编码负转录因子的基因，显示出与体裂相对应的周期性表达。在此之前，我们发现Hes7对于躯体发育和周期性基因表达都是必不可少的。在本研究中，我们发现Hes7蛋白周期性地抑制周期基因的启动子，并建立一个负反馈回路作为2小时周期的生物钟的主要机制。此外，我们产生了具有更长的半衰期的Hes7突变小鼠，并证明了Hes7蛋白的不稳定性对于基因表达的持续振荡至关重要。因此，控制体体周期性分割的生物钟依赖于体前中胚层细胞中Hes7的负反馈回路和Hes7蛋白的快速降解。

项目成果

Identification of a novel basic helix-loop-helix gene, Heslike, and its role in GABAergic Neurogenesis

• DOI: 10.1523/jneurosci.5327-03.2004
• 发表时间: 2004-04-07
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Miyoshi, G;Bessho, Y;Kageyama, R
• 通讯作者: Kageyama, R

体節形成と時計 発生生物学がわかる

了解体节形成和生物钟的发育生物学

• 发表时间: 2004
• 作者: Sakamoto;M;別所康全
• 通讯作者: 別所康全

Mouse Fbw7/Se1-10/Cdc4 is required for notch degradation during vascular development

血管发育过程中缺口降解需要小鼠 Fbw7/Se1-10/Cdc4

• 发表时间: 2004
• 期刊: J Biol Chem 279
• 作者: Tsunematsu;R
• 通讯作者: R

Requirement of multiple bHLH genes for retinal neuronal subtype specification

视网膜神经元亚型规范需要多个 bHLH 基因

• 发表时间: 2004
• 期刊: J Biol Chem 279
• 作者: Akagi;T
• 通讯作者: T

Bessho, Y., et al.: "Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock"Genes & Dev.. 17. 1451-1456 (2003)

Bessho, Y. 等人：“bHLH 因子 Hes7 的周期性抑制是体节分段时钟的重要机制”基因