Mathematical models for the Notch and Wnt signaling pathways and the crosstalk between them during somitogenesis

Abstract

BackgroundSomitogenesis is a fundamental characteristic feature of development in various animal embryos. Molecular evidence has proved that the Notch and Wnt pathways play important roles in regulating the process of somitogenesis and there is crosstalk between these two pathways. However, it is difficult to investigate the detailed mechanism of these two pathways and their interactions in somitogenesis through biological experiments. In recent years some mathematical models have been proposed for the purpose of studying the dynamics of the Notch and Wnt pathways in somitogenesis. Unfortunately, only a few of these models have explored the interactions between them.ResultsIn this study, we have proposed three mathematical models for the Notch signalling pathway alone, the Wnt signalling pathway alone, and the interactions between them. These models can simulate the dynamics of the Notch and Wnt pathways in somitogenesis, and are capable of reproducing the observations derived from wet experiments. They were used to investigate the molecular mechanisms of the Notch and Wnt pathways and their crosstalk in somitogenesis through the model simulations.ConclusionsThree mathematical models are proposed for the Notch and Wnt pathways and their interaction during somitogenesis. The simulations demonstrate that the extracellular Notch and Wnt signals are essential for the oscillating expressions of both Notch and Wnt target genes. Moreover, the internal negative feedback loops and the three levels of crosstalk between these pathways play important but distinct roles in maintaining the system oscillation. In addition, the results of the parameter sensitivity analysis of the models indicate that the Notch pathway is more sensitive to perturbation in somitogenesis.

Efficient Differentiation of Human Pluripotent Stem Cells to Endothelial Progenitors via Small-Molecule Activation of WNT Signaling

“…GSK3 inhibition has been shown to be a potent inducer of mesendoderm lineage commitment in hPSCs ( Tan et al., 2013 ). The WNT pathway exhibits crosstalk with a variety of other developmental signaling networks, including TGF-β superfamily ( Cai et al., 2013 ), FGF ( Stulberg et al., 2012 ), Notch ( Wang et al., 2013 ), Hippo ( Hergovich and Hemmings, 2010 ), and retinoic acid signaling ( Chanda et al., 2013 ). The necessity of β-catenin in generating CD34 + CD31 + cells indicates a direct role of canonical WNT signaling in endothelial progenitor differentiation, whereas the diminished yield of CD34 + CD31 + cells in the presence of MEK and receptor tyrosine kinase inhibitors suggests endogenous pathways also mediate endothelial progenitor differentiation.…”

The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt

“…However, this pared-down approach cannot represent subcellular details of the crosstalk. Existing mathematical models at the subcellular scale have accounted for interactions between GSK3β and NICD [56], between NICD and Dsh [57] or via LEF/TCF and membrane-bound Notch, in which inhibition of Wnt is used to drive terminal differentiation [58,59]. Some of these models omit a Hes1 autoregulation motif [58,59] and indeed, few multicellular studies of the role of Hes1 oscillations in cell fate exist at the present time.…”

Modelling Coupled Oscillations in the Notch, Wnt, and FGF Signaling Pathways during Somitogenesis: A Comprehensive Mathematical Model

“…Based on our previous work [ 17 ] and the model of the FGF pathway proposed by Goldbeter and Pourquié [ 14 ], we established a more comprehensive crosstalk model for the Notch, Wnt, and FGF pathways in the segmentation clock. A schematic diagram of the model is shown in Figure 1 .…”

“…In 2012, Tiedemann et al presented an enhanced gene regulatory network model for the growing PSM of mice by many virtual cells and integrated Wnt3a and FGF8 gradient formation, periodic gene expression, and Delta/Notch signaling [ 16 ]. In 2013, our research group also proposed a crosstalk model, which contains multiple levels of crosstalk between the Notch and Wnt pathways [ 17 ]. Our model elucidated the mechanisms of the Notch and Wnt target genes' oscillatory expression, and the crosstalk mechanisms between the Notch and Wnt pathways.…”