Short-lived Her proteins drive robust synchronized oscillations in the zebrafish segmentation clock
Short-lived Her proteins drive robust synchronized oscillations in the zebrafish segmentation clock
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DOI：
10.1242/dev.093278
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发表时间：
2013-08-01
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;Knierer, Stephan;Oezbudak, Ertugrul M.
振荡在自然系统中很普遍。基因表达振荡器，称为分割时钟，控制脊柱前体的分割。属于Hes/her家族的基因编码了所有被分析的脊椎动物物种中唯一保守的振荡基因。he /Her蛋白形成二聚体并负向自动调节自身的转录。在这里，我们开发了一个随机的二维多细胞计算模型来阐明如何调节分割时钟的动态，即周期，幅度和同步。我们进行了参数搜索，以证明冗余抑制因子Her二聚体的自调节负反馈回路可以在野生型胚胎中产生同步的基因表达振荡，并再现了不同突变条件下分割振荡的动态。我们的模型还预测，只要抑制二聚体的半衰期短于6分钟，就可以稳定地产生同步振荡。我们首次通过测量Her7蛋白的半衰期为3.5分钟来验证这一预测。这些结果证明了建立生物学上真实的随机模型对于更严格地测试生物学模型和为未来的实验研究做出预测的重要性。
Oscillations are prevalent in natural systems. A gene expression oscillator, called the segmentation clock, controls segmentation of precursors of the vertebral column. Genes belonging to the Hes/her family encode the only conserved oscillating genes in all analyzed vertebrate species. Hes/Her proteins form dimers and negatively autoregulate their own transcription. Here, we developed a stochastic two-dimensional multicellular computational model to elucidate how the dynamics, i.e. period, amplitude and synchronization, of the segmentation clock are regulated. We performed parameter searches to demonstrate that autoregulatory negative-feedback loops of the redundant repressor Her dimers can generate synchronized gene expression oscillations in wild-type embryos and reproduce the dynamics of the segmentation oscillator in different mutant conditions. Our model also predicts that synchronized oscillations can be robustly generated as long as the half-lives of the repressor dimers are shorter than 6 minutes. We validated this prediction by measuring, for the first time, the half-life of Her7 protein as 3.5 minutes. These results demonstrate the importance of building biologically realistic stochastic models to test biological models more stringently and make predictions for future experimental studies.