Goldbeter Albert, Pourquié Olivier
Faculté des Sciences, Université Libre de Bruxelles, Campus Plaine, C.P. 231, B-1050 Brussels, Belgium.
J Theor Biol. 2008 Jun 7;252(3):574-85. doi: 10.1016/j.jtbi.2008.01.006. Epub 2008 Jan 18.
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, Wnt 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 Wnt 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.
在脊椎动物分节过程中，体节的形成受一种称为分节时钟的振荡器调控，该振荡器的周期根据生物体不同，在30分钟到数小时之间。这个振荡器能使前体节中胚层的连续细胞群响应分节时钟发出的周期性信号，同步激活分节基因，从而确定未来的体节。最近的微阵列实验[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]表明，Notch、Wnt和成纤维细胞生长因子（FGF）信号通路参与了分节时钟的机制。通过计算建模，我们研究了这三条信号通路中持续振荡发生的条件。首先，我们表明Lunatic Fringe蛋白对细胞内Notch激活的负反馈可导致Notch通路中的周期性行为。然后我们表明，Axin2通过形成Axin2破坏复合物对β-连环蛋白降解施加的负反馈可在Wnt通路中产生振荡。同样，由基因MKP3/Dusp6的磷酸酶产物介导的对FGF信号的负反馈可在FGF通路中产生振荡基因表达。通过共同中间体耦合Wnt、Notch和FGF振荡器，根据三条通路中振荡的相对周期，可导致三条信号通路中的同步振荡或复杂的周期性行为。三条通路中循环基因之间的相位关系取决于通路之间耦合的性质及其相对自主周期。该模型提供了一个框架，用于根据涉及Wnt、Notch和FGF信号通路的振荡模块网络来分析分节时钟的动态。
