Spatial gradients of protein-level time delays set the pace of the traveling segmentation clock waves
Spatial gradients of protein-level time delays set the pace of the traveling segmentation clock waves
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DOI：
10.1242/dev.111930
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发表时间：
2014-11-01
期刊：
影响因子：
4.6
通讯作者：
Oezbudak, Ertugrul M.
中科院分区：
文献类型：
--
作者：
Ay, Ahmet;Holland, Jack;Oezbudak, Ertugrul M.
脊椎动物分段时钟是在胚胎发育过程中控制脊柱节律分段的基因表达振荡器。当细胞沿着后轴移动到前轴时，振荡周期变得更长，这导致时钟基因表达的行波扫过未分段的组织。尽管已经提出了需要将额外的调控基因纳入不同空间位置的核心时钟网络的各种假设，但行波背后的机制仍然难以捉摸。在这里，我们结合分子水平计算模型和定量实验来解决这个难题。我们的模型预测基因表达时间延迟沿后向前方向存在递增梯度，以概括斑马鱼不同遗传背景中行进分段时钟波的时空分布。我们通过测量沿未分段组织振荡 Her1 蛋白产生的时间延迟增加来验证这一预测。我们的结果驳斥了核心反馈环路空间扩展来解释行波发生的必要性。基因表达时间延迟的空间调控是创建动态模式的一种新方法；这是第一份证明任何组织中存在这种控制机制的报告，未来的研究将探索其他生物系统中是否存在类似的例子。
The vertebrate segmentation clock is a gene expression oscillator controlling rhythmic segmentation of the vertebral column during embryonic development. The period of oscillations becomes longer as cells are displaced along the posterior to anterior axis, which results in traveling waves of clock gene expression sweeping in the unsegmented tissue. Although various hypotheses necessitating the inclusion of additional regulatory genes into the core clock network at different spatial locations have been proposed, the mechanism underlying traveling waves has remained elusive. Here, we combined molecular-level computational modeling and quantitative experimentation to solve this puzzle. Our model predicts the existence of an increasing gradient of gene expression time delays along the posterior to anterior direction to recapitulate spatiotemporal profiles of the traveling segmentation clock waves in different genetic backgrounds in zebrafish. We validated this prediction by measuring an increased time delay of oscillatory Her1 protein production along the unsegmented tissue. Our results refuted the need for spatial expansion of the core feedback loop to explain the occurrence of traveling waves. Spatial regulation of gene expression time delays is a novel way of creating dynamic patterns; this is the first report demonstrating such a control mechanism in any tissue and future investigations will explore the presence of analogous examples in other biological systems.