title: Spatio-temporal model of endogenous ROS and raft-dependent WNT/beta-catenin signaling driving cell fate commitment in human neural progenitor cells.
abstract: Canonical WNT/β-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/β-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 β-catenin levels during the cell fate commitment phase of neural differentiation. We find that the biphasic activation of β-catenin signaling observed experimentally can only be explained through a model that combines Reactive Oxygen Species (ROS) and raft dependent WNT/β-catenin signaling. Accordingly after initiation of differentiation endogenous ROS activates DVL in a redox-dependent manner leading to a transient activation of down-stream β-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/β-catenin signal or as amplifier during continuous auto-/parcrine WNT/β-catenin signaling. In addition we provide the first stochastic computational model of WNT/β-catenin signaling that combines membrane-related and intracellular processes, including lipid rafts/receptor dynamics as well as WNT- and ROS-dependent β-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/β-catenin signaling and the role of ROS as intracellular signaling mediator.
authors: Modeling and Simulation Group, Institute of Computer Science, University of Rostock, Rostock, Germany.
authors: Fiete
authors: F
authors: Haack
authors: Live Cell Imaging Center, Institute of Biological Sciences, University of Rostock, Rostock, Germany; Reference and Translation Center for Cardiac Stem Cell Therapy (RTC), University Medical Center Rostock, Rostock, Germany.
authors: Heiko
authors: H
authors: Lemcke
authors: Modeling and Simulation Group, Institute of Computer Science, University of Rostock, Rostock, Germany.
authors: Roland
authors: R
authors: Ewald
authors: Live Cell Imaging Center, Institute of Biological Sciences, University of Rostock, Rostock, Germany; Electrochemical Signaling in Development and Disease, Max-Delbrück-Center for Molecular Medicine (MDC) Berlin-Buch, Berlin-Buch, Germany.
authors: Tareck
authors: T
authors: Rharass
authors: Modeling and Simulation Group, Institute of Computer Science, University of Rostock, Rostock, Germany.
authors: Adelinde M
authors: AM
authors: Uhrmacher
mesh_terms: D002460:Cell Line; D019295:Computational Biology; D003198:Computer Simulation; D006801:Humans; D058953:Neural Stem Cells / Q000378:metabolism* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015203:Reproducibility of Results; D062211:Spatio-Temporal Analysis; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D051153:Wnt Proteins; D051176:beta Catenin