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Spatio-temporal model of endogenous ROS and raft-dependent WNT/β-catenin signaling driving cell fate commitment in human neural progenitor cells

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Item Type:Article
Title:Spatio-temporal model of endogenous ROS and raft-dependent WNT/β-catenin signaling driving cell fate commitment in human neural progenitor cells
Creators Name:Haack, F. and Lemcke, H. and Ewald, R. and Rharass, T. and Uhrmacher, A.M.
Abstract:Canonical WNT/{beta}-catenin signaling is a central pathway in embryonic development, but it is also connected to a number of cancers and developmental disorders. Here we apply a combined in-vitro and in-silico approach to investigate the spatio-temporal regulation of WNT/{beta}-catenin signaling during the early neural differentiation process of human neural progenitors cells (hNPCs), which form a new prospect for replacement therapies in the context of neurodegenerative diseases. Experimental measurements indicate a second signal mechanism, in addition to canonical WNT signaling, being involved in the regulation of nuclear {beta}-catenin levels during the cell fate commitment phase of neural differentiation. We find that the biphasic activation of {beta}-catenin signaling observed experimentally can only be explained through a model that combines Reactive Oxygen Species (ROS) and raft dependent WNT/{beta}-catenin signaling. Accordingly after initiation of differentiation endogenous ROS activates DVL in a redox-dependent manner leading to a transient activation of down-stream {beta}-catenin signaling, followed by continuous auto/paracrine WNT signaling, which crucially depends on lipid rafts. Our simulation studies further illustrate the elaborate spatio-temporal regulation of DVL, which, depending on its concentration and localization, may either act as direct inducer of the transient ROS/{beta}-catenin signal or as amplifier during continuous auto-/parcrine WNT/{beta}-catenin signaling. In addition we provide the first stochastic computational model of WNT/{beta}-catenin signaling that combines membrane-related and intracellular processes, including lipid rafts/receptor dynamics as well as WNT- and ROS-dependent {beta}-catenin activation. The model's predictive ability is demonstrated under a wide range of varying conditions for in-vitro and in-silico reference data sets. Our in-silico approach is realized in a multi-level rule-based language, that facilitates the extension and modification of the model. Thus, our results provide both new insights and means to further our understanding of canonical WNT/{beta}-catenin signaling and the role of ROS as intracellular signaling mediator.
Keywords:Cell Line, Computational Biology, Computer Simulation, Neural Stem Cells, Reactive Oxygen Species, Reproducibility of Results, Spatio-Temporal Analysis, Wnt Proteins, Wnt Signaling Pathway, {beta} Catenin
Source:PLoS Computational Biology
Publisher:Public Library of Science
Page Range:e1004106
Date:20 March 2015
Official Publication:https://doi.org/10.1371/journal.pcbi.1004106
PubMed:View item in PubMed

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