Instability of Hes7 protein is crucial for the somite segmentation clock
Instability of Hes7 protein is crucial for the somite segmentation clock
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DOI：
10.1038/ng1372
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发表时间：
2004-07-01
期刊：
影响因子：
30.8
通讯作者：
Kageyama, R
中科院分区：
文献类型：
--
作者：
Hirata, H;Bessho, Y;Kageyama, R
在小鼠胚胎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萌发出来，这表明体节的分割是由一个2小时周期(1-3)的生物钟控制的。作为Notch信号的效应因子，基本螺旋-环-螺旋因子Hes7的表达遵循负反馈控制的2小时振荡周期，这被认为是体节分割时钟(4-6)的分子基础。如果这一提议是正确的，那么这个时钟应该主要取决于Hes7的短暂寿命。为了解决Hes7不稳定性的生物学重要性，我们培育了表达突变体Hes7的小鼠，半衰期更长(野生型Hes7的半衰期类似于30分钟，而野生型Hes7的半衰期类似于22分钟)，但抑制物活性正常。在这些小鼠中，体节分割和振荡表达在几个正常的分割周期后变得严重混乱。我们使用直接自抑制模型对这种影响进行了数学模拟。因此，Hes7的不稳定性对于持续的振荡和作为分段时钟的功能是必不可少的。
During somitogenesis, a pair of somites buds off from the presomitic mesoderm every 2 hours in mouse embryos, suggesting that somite segmentation is controlled by a biological clock with a 2-hour cycle(1-3). Expression of the basic helix-loop-helix factor Hes7, an effector of Notch signaling, follows a 2-hour oscillatory cycle controlled by negative feedback; this is proposed to be the molecular basis for the somite segmentation clock(4-6). If the proposal is correct, this clock should depend crucially on the short lifetime of Hes7. To address the biological importance of Hes7 instability, we generated mice expressing mutant Hes7 with a longer half-life (similar to30 min compared with similar to22 min for wild-type Hes7) but normal repressor activity. In these mice, somite segmentation and oscillatory expression became severely disorganized after a few normal cycles of segmentation. We simulated this effect mathematically using a direct autorepression model. Thus, instability of Hes7 is essential for sustained oscillation and for its function as a segmentation clock.