Topology and dynamics of the zebrafish segmentation clock core circuit.
Topology and dynamics of the zebrafish segmentation clock core circuit.
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DOI：
10.1371/journal.pbio.1001364
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发表时间：
2012
期刊：
影响因子：
9.8
通讯作者：
Oates AC
中科院分区：
文献类型：
--
作者：
Schröter C;Ares S;Morelli LG;Isakova A;Hens K;Soroldoni D;Gajewski M;Jülicher F;Maerkl SJ;Deplancke B;Oates AC
通过结合生物化学，胚胎学和数学方法，这项工作揭示了蛋白质-蛋白质相互作用在确定脊椎动物体节形成分割时钟的动态中的重要作用。在脊椎动物胚胎发育过程中，体轴的节律性和顺序性分节是由一个振荡的遗传网络（称为分节时钟）调节的。我们描述了一个新的动态模型的核心起搏电路的斑马鱼分割时钟的基础上系统的生化研究网络的拓扑结构和精确测量的体节发生动态的新的遗传突变体。我们发现，核心起搏电路由两个不同的负反馈回路，一个与Her 1同源二聚体和其他与Her 7：Hes 6异源二聚体，并行操作。为了解释在我们的动态模型中观察到的her 1，her 7和hes 6突变胚胎的单突变和双突变表型，我们假设具有DNA结合活性的二聚体的可用性和有效稳定性被控制在“二聚体云”中，该“二聚体云”包含三个因素之间所有可能的二聚体组合。我们的模型的这一特征预测，尽管hes 6 mRNA的产生是恒定的，但Hes 6蛋白水平应该振荡，我们使用新型Hes 6抗体通过实验证实了这一点。由具有和不具有DNA结合活性的二聚体群体控制电路的动力学是分段时钟的新原理，并且可能与其他生物钟和转录调控网络相关。脊柱的分段模式是脊椎动物身体的定义特征之一，在胚胎发育期间建立。胚胎的体节，称为体节，从头到尾顺序和有节奏地形成。体节形成的周期性由体节时钟（segmentation clock）调节，体节时钟是一种在最后胚胎组织中滴答作响的遗传振荡器：对于时钟的每一个滴答声，都会产生一对新的双侧体节。时钟的周期似乎决定了片段的数量和长度，但是什么控制着这个周期呢？在这篇文章中，我们研究了三个转录因子的相互作用，形成时钟的调节电路的核心，并测量了如何分割的周期变化时，这些因素单独或组合突变。我们发现，这三个因素有助于“二聚体云”，其中包含所有可能的二聚体组合，然而，只有两个二聚体在这个云可以结合DNA，这使得他们能够直接调节振荡基因的表达，支撑节段形成的周期性。然而，基于我们的实验结果的时钟的动力学的数学模型表明，非DNA结合的二聚体也影响稳定性，因此功能，两个DNA结合的二聚体控制分割时钟的周期。这种非DNA结合二聚体的参与是分段时钟的一种新的调节原理，这也可能是在其他生物钟中运行的一般机制。
By combining biochemical, embryological, and mathematical approaches, this work uncovers an important role for protein-protein interactions in determining the dynamics of the somite-forming segmentation clock in vertebrates. During vertebrate embryogenesis, the rhythmic and sequential segmentation of the body axis is regulated by an oscillating genetic network termed the segmentation clock. We describe a new dynamic model for the core pace-making circuit of the zebrafish segmentation clock based on a systematic biochemical investigation of the network's topology and precise measurements of somitogenesis dynamics in novel genetic mutants. We show that the core pace-making circuit consists of two distinct negative feedback loops, one with Her1 homodimers and the other with Her7:Hes6 heterodimers, operating in parallel. To explain the observed single and double mutant phenotypes of her1, her7, and hes6 mutant embryos in our dynamic model, we postulate that the availability and effective stability of the dimers with DNA binding activity is controlled in a “dimer cloud” that contains all possible dimeric combinations between the three factors. This feature of our model predicts that Hes6 protein levels should oscillate despite constant hes6 mRNA production, which we confirm experimentally using novel Hes6 antibodies. The control of the circuit's dynamics by a population of dimers with and without DNA binding activity is a new principle for the segmentation clock and may be relevant to other biological clocks and transcriptional regulatory networks. The segmented pattern of the vertebral column, one of the defining features of the vertebrate body, is established during embryogenesis. The embryo's segments, called somites, form sequentially and rhythmically from head to tail. The periodicity of somite formation is regulated by the segmentation clock, a genetic oscillator that ticks in the posterior-most embryonic tissue: for each tick of the clock, one new bilateral pair of segments is made. The period of the clock appears to determine the number and the length of segments, but what controls this periodicity? In this article, we have investigated the interactions of three transcription factors that form the core of the clock's regulatory circuit, and have measured how the period of segmentation changes when these factors are mutated alone or in combination. We find that these three factors contribute to a “dimer cloud” that contains all possible dimeric combinations; however, only two dimers in this cloud can bind DNA, which allows them to directly regulate the oscillatory gene expression that underpins the periodicity of segment formation. Nevertheless, a mathematical model of the clock's dynamics based on our experimental findings indicates that the non-DNA-binding dimers also influence the stability, and hence the function, of the two DNA-binding dimers controlling the segmentation clock's period. Such involvement of non-DNA-binding dimers is a novel regulatory principle for the segmentation clock, which might also be a general mechanism that operates in other biological clocks.
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影响因子：
5.6
作者：
Buchler, Nicolas E.;Louis, Matthieu
通讯作者：
Louis, Matthieu
影响因子：
4.3
作者：
Campanelli M;Gedeon T
通讯作者：
Gedeon T
广泛表达的HLH基因的网络调节组织特异性细胞命运。
影响因子：
64.5
作者：
Bhattacharya A;Baker NE
通讯作者：
Baker NE
DOI：
10.1073/pnas.0409553102
发表时间：
2005-07-05
影响因子：
11.1
作者：
Buchler, NE;Gerland, U;Hwa, T
通讯作者：
Hwa, T
影响因子：
4.3
作者：
Cinquin, Olivier
通讯作者：
Cinquin, Olivier