Parameter-free methods distinguish Wnt pathway models and guide design of experiments
KAUST Grant NumberKUK-C1-013-04
Online Publication Date2015-02-17
Print Publication Date2015-03-03
Permanent link to this recordhttp://hdl.handle.net/10754/599139
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AbstractThe canonical Wnt signaling pathway, mediated by β-catenin, is crucially involved in development, adult stem cell tissue maintenance, and a host of diseases including cancer. We analyze existing mathematical models of Wnt and compare them to a new Wnt signaling model that targets spatial localization; our aim is to distinguish between the models and distill biological insight from them. Using Bayesian methods we infer parameters for each model from mammalian Wnt signaling data and find that all models can fit this time course. We appeal to algebraic methods (concepts from chemical reaction network theory and matroid theory) to analyze the models without recourse to specific parameter values. These approaches provide insight into aspects of Wnt regulation: the new model, via control of shuttling and degradation parameters, permits multiple stable steady states corresponding to stem-like vs. committed cell states in the differentiation hierarchy. Our analysis also identifies groups of variables that should be measured to fully characterize and discriminate between competing models, and thus serves as a guide for performing minimal experiments for model comparison.
CitationMacLean AL, Rosen Z, Byrne HM, Harrington HA (2015) Parameter-free methods distinguish Wnt pathway models and guide design of experiments. Proc Natl Acad Sci USA 112: 2652–2657. Available: http://dx.doi.org/10.1073/pnas.1416655112.
SponsorsWe thank A. Burgess and C. Wee Tan for data and discussions about Wnt signaling. We also thank the anonymous reviewers as well as T. Dale, E. Feliu, A. Fletcher, K. Ho, P. K. Maini, E. O’Neill, A. Shiu, and B. Sturmfels for helpful discussions and/or comments on the manuscript. H.A.H. gratefully acknowledges funding from Engineering and Physical Sciences Research Council Fellowship EP/K041096/1 and the American Institute of Mathematics. Z.R. and H.A.H. acknowledge funding from Royal Society International Exchanges Scheme 2014/R1 IE140219. A.L.M. and H.M.B. acknowledge funding from the Human Frontiers in Science Program (RGP0039/2011). A.L.M., H.M.B., and H.A.H. acknowledge funding from King Abdullah University of Science and Technology KUK-C1-013-04.
PubMed Central IDPMC4352827
CollectionsPublications Acknowledging KAUST Support
- Algebraic Systems Biology: A Case Study for the Wnt Pathway.
- Authors: Gross E, Harrington HA, Rosen Z, Sturmfels B
- Issue date: 2016 Jan
- Mathematical and Statistical Techniques for Systems Medicine: The Wnt Signaling Pathway as a Case Study.
- Authors: MacLean AL, Harrington HA, Stumpf MP, Byrne HM
- Issue date: 2016
- Wnt5a and Wnt11 inhibit the canonical Wnt pathway and promote cardiac progenitor development via the Caspase-dependent degradation of AKT.
- Authors: Bisson JA, Mills B, Paul Helt JC, Zwaka TP, Cohen ED
- Issue date: 2015 Feb 1
- Retinoic acid suppresses the canonical Wnt signaling pathway in embryonic stem cells and activates the noncanonical Wnt signaling pathway.
- Authors: Osei-Sarfo K, Gudas LJ
- Issue date: 2014 Aug
- Targeting the canonical Wnt/β-catenin pathway in hematological malignancies.
- Authors: Ashihara E, Takada T, Maekawa T
- Issue date: 2015 Jun