Modeling the segmentation clock as a network of coupled oscillations in the Notch, Wnt and FGF signaling pathways
Modeling the segmentation clock as a network of coupled oscillations in the Notch, Wnt and FGF signaling pathways
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DOI：
10.1016/j.jtbi.2008.01.006
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发表时间：
2008-06-07
影响因子：
2
通讯作者：
Pourquie, Olivier
中科院分区：
文献类型：
--
作者：
Goldbeter, Albert;Pourquie, Olivier
脊椎动物体节的形成是由一个被称为体节时钟的振荡器控制的，其特征在于取决于生物体的30分钟到几个小时的周期。该振荡器允许同步激活分裂前中胚层中连续细胞群中的分裂基因，以响应由分裂时钟发出的周期性信号，从而定义未来的片段。最近的微阵列实验[Dequeant，M.L.，Glynn，E.，Gaudenz，K.，Wahl，M.，陈杰，Mushegian，A.，Pourquie，O.，2006.一个复杂的信号基因振荡网络是小鼠分割时钟的基础。Science 314，1595-1598]表明Notch、Writ和成纤维细胞生长因子（FGF）信号传导途径参与了分割时钟的机制。通过计算建模，我们调查的条件下，持续振荡发生在这三个信号通路。首先，我们表明，负反馈介导的Lunatic Fringe蛋白对细胞内的Notch激活可以引起周期性行为的Notch途径。然后，我们表明，通过Axin 2破坏复合物的形成，Axin 2对β-连环蛋白降解产生的负反馈可以在Writ途径中产生振荡。同样，由基因MKP 3/Dusp 6的磷酸酶产物介导的FGF信号传导的负反馈可以在FGF途径中产生振荡基因表达。通过共同的中间体偶联Wnt、Notch和FGF振荡器可以导致三种信号传导途径中的同步振荡或复杂的周期性行为，这取决于三种途径中振荡的相对周期。在三个途径中的循环基因之间的相位关系取决于途径之间的耦合的性质和它们的相对自主周期。该模型提供了一个框架，用于分析的动态分割时钟的振荡模块涉及Wnt，Notch和FGF信号通路的网络。(c)2008爱思唯尔有限公司保留所有权利。
The formation of somites in the course of vertebrate segmentation is governed by an oscillator known as the segmentation clock, which is characterized by a period ranging from 30 min to a few hours depending on the organism. This oscillator permits the synchronized activation of segmentation genes in successive cohorts of cells in the presomitic mesoderm in response to a periodic signal emitted by the segmentation clock, thereby defining the future segments. Recent microarray experiments [Dequeant, M.L., Glynn, E., Gaudenz, K., Wahl, M., Chen, J., Mushegian, A., Pourquie, O., 2006. A complex oscillating network of signaling genes underlies the mouse segmentation clock. Science 314, 1595-1598] indicate that the Notch, Writ and Fibroblast Growth Factor (FGF) signaling pathways are involved in the mechanism of the segmentation clock. By means of computational modeling, we investigate the conditions in which sustained oscillations occur in these three signaling pathways. First we show that negative feedback mediated by the Lunatic Fringe protein on intracellular Notch activation can give rise to periodic behavior in the Notch pathway. We then show that negative feedback exerted by Axin2 on the degradation of beta-catenin through formation of the Axin2 destruction complex can produce oscillations in the Writ pathway. Likewise, negative feedback on FGF signaling mediated by the phosphatase product of the gene MKP3/Dusp6 can produce oscillatory gene expression in the FGF pathway. Coupling the Wnt, Notch and FGF oscillators through common intermediates can lead to synchronized oscillations in the three signaling pathways or to complex periodic behavior, depending on the relative periods of oscillations in the three pathways. The phase relationships between cycling genes in the three pathways depend on the nature of the coupling between the pathways and on their relative autonomous periods. The model provides a framework for analyzing the dynamics of the segmentation clock in terms of a network of oscillating modules involving the Wnt, Notch and FGF signaling pathways. (c) 2008 Elsevier Ltd. All rights reserved.