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, Jul 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.
    International Journal of Engineering Science 10/2014; 83. DOI:10.1016/j.ijengsci.2014.05.003 · 2.29 Impact Factor
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    • "negative feedback via Axin-2 or Dickkopf (DKK) are prominent examples that have been investigated both experimentally (Leung et al., 2002; Lustig et al., 2002; Niida et al., 2004) and theoretically (Wawra et al., 2007; Goldbeter and Pourquie, 2008; Jensen et al., 2010). Here, we concentrate on possible transcriptional feedbacks via TCF family members (Roose et al., 1999; Hovanes et al., 2001; Saegusa et al., 2005; Vadlamudi et al., 2005; Driskell et al., 2007). "
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    ABSTRACT: The Wnt/β-catenin pathway is involved in the regulation of a multitude of physiological processes by controlling the differential expression of target genes. In certain tissues such as the adult liver, the Wnt/β-catenin pathway can attain different levels of activity due to gradients of Wnt ligands and/or intracellular pathway components like APC. How graded pathway activity is converted into regionally distinct patterns of Wnt/β-catenin target gene expression is largely unknown. Here, we apply a mathematical modeling approach to investigate the impact of different regulatory mechanisms on target gene expression within Wnt or APC concentration gradients. We develop a minimal model of Wnt/β-catenin signal transduction and combine it with various mechanisms of target gene regulation. In particular, the effects of activation, inhibition, and an incoherent feedforward loop (iFFL) are compared. To specify activation kinetics, we analyze experimental data that quantify the response of β-catenin/TCF reporter constructs to different Wnt concentrations, and demonstrate that the induction of these constructs occurs in a cooperative manner with Hill coefficients between 2 and 5. In summary, our study shows that the combination of specific gene regulatory mechanisms with a time-independent gradient of Wnt or APC is sufficient to generate distinct target gene expression patterns as have been experimentally observed in liver. We find that cooperative gene activation in combination with a TCF feedback can establish sharp borders of target gene expression in Wnt or APC gradients. In contrast, the iFFL renders gene expression independent of gradients of the upstream signaling components. Our subsequent analysis of carcinogenic pathway mutations reveals that their impact on gene expression is determined by the gene regulatory mechanism and the APC concentration of the cell in which the mutation occurs.
    Frontiers in Physiology 02/2013; 4:21. DOI:10.3389/fphys.2013.00021 · 3.50 Impact Factor
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    • "This, essentially macroscopic point of view in no way neglects the ingenious schemes of molecular level regulation of a segmentation process (e.g. Goldbeter and Pourquié, 2008) but urges to explore in more details the interrelations of the molecular and cellular levels events: do the first ones fully determine the latter, or the reverse effects are also possible? Limb development is a very attractive task for morphomechanics . "
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    ABSTRACT: We start from reviewing different epistemological constructions used for explaining morphogenesis. Among them, we explore the explanatory power of a law-centered approach which includes top-down causation and the basic concepts of a self-organization theory. Within such a framework, we discuss the morphomechanical models based upon the presumption of feedbacks between mechanical stresses imposed onto a given embryo part from outside and those generated within the latter as a kind of active response. A number of elementary morphogenetic events demonstrating that these feedbacks are directed towards hyper-restoration (restoration with an overshoot) of the initial state of mechanical stresses are described. Moreover, we show that these reactions are bound together into the larger scale feedbacks. That permits to suggest a reconstruction of morphogenetic successions in early Metazoan development concentrated around two main archetypes distinguished by the blastopores geometry. The perspectives of applying the same approach to cell differentiation are outlined. By discussing the problem of positional information we suggest that the developmental pathway of a given embryo part depends upon its preceded deformations and the corresponding mechanical stresses rather than upon its static position at any moment of development.
    Bio Systems 05/2012; 109(3):262-79. DOI:10.1016/j.biosystems.2012.05.003 · 1.47 Impact Factor
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