Article

Modeling the segmentation clock as a network of coupled oscillations in the Notch, Wnt and FGF signaling pathways

Faculté des Sciences, Université Libre de Bruxelles, Campus Plaine, C.P. 231, B-1050 Brussels, Belgium.
Journal of Theoretical Biology (Impact Factor: 2.3). 07/2008; 252(3):574-85. DOI: 10.1016/j.jtbi.2008.01.006
Source: PubMed

ABSTRACT 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.

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Available from: Albert Goldbeter, Aug 31, 2015
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    • "The underlying biochemical mechanism, known as the 'clock and wave-front' model (see Fig. 1), has been substantiated by the identification of both: genes that oscillate (Li, Fenger, Niehrs, & Pollet, 2003; Palmeirim, Henrique, Ish-Horowicz, & Pourquié, 1997; Schröter et al., 2012), and diffusion gradients of morphogens that propagate along the body axis (Dubrulle & Pourquié, 2002; Kicheva, Bollenbach, Wartlick, Jülicher, & Gonzalez-Gaitan, 2012). The long range synchronization issue for independent genetic oscillators has also been addressed and various components have been integrated into a comprehensive network model (Baker, Schnell, & Maini, 2008; Goldbeter & Pourquié, 2008; Hester et al., 2011). Even though the 'clock and wavefront' model does not specify how the finite blocks of cells undergo synchronized consolidation into somites, it is supported by the observations that mutations to some of the proposed genetic candidates alter the period of somitogenesis and affect the total number of somites in the body (Harima et al., 2013; Herrgen et al., 2010; Kim et al., 2011; Schröter et al., 2012). "
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    ABSTRACT: Segmentation is a characteristic feature of the vertebrate body plan. The prevailing paradigm explaining its origin is the ‘clock and wave-front’ model, which assumes that the interaction of a molecular oscillator (clock) with a traveling gradient of morphogens (wave) pre-defines spatial periodicity. While many genes potentially responsible for these processes have been identified, the precise role of molecular oscillations and the mechanism leading to physical separation of the somites remain elusive. In this paper we argue that the periodicity along the embryonic body axis anticipating somitogenesis is controlled by mechanical rather than bio-chemical signaling. Using a prototypical model we show that regular patterning can result from a mechanical instability induced by differential strains developing between the segmenting mesoderm and the surrounding tissues. The main ingredients of the model are the assumptions that cell–cell adhesions soften when overstretched, and that there is an internal length scale defining the cohesive properties of the mesoderm. The proposed mechanism generates a robust number of segments without dependence on genetic oscillations.
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    • "Mathematical models have been proposed based on this mechanism for the transcriptional regulation that generates oscillatory gene expression in the somite segmentation clock10111213. Of these, a mathematical model that directed the negative feedback loop of a transcription factor with its time delay successfully reproduced oscillatory gene expression1213. "
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    • "In SB623 cells, we observed a profound downregulation of FGF receptor FGFR2 and a mild, but reproducible, downregulation of FGFR1 expression. FGFR1 and FGFR2 are major FGF receptors expressed by cultured MSCs [31], and their downregulation may signify several things: (a) it can explain the slower growth of SB623 cells compared with MSCs [10], (b) it can be a senescence-associated trait [31]; (c) it can drastically reduce the FGF uptake by SB623 cells, thus increasing the FGF availability to the surrounding neural cells; (d) it may also represent a negative-feedback mechanism triggered by the forced expression of the exogenous NICD1 [32], a hypothesis that must be explored in subsequent studies. "
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