Cross-talk between Hippo and Wnt signalling pathways in intestinal crypts: Insights from an agent-based model
| Autor: | Alexander G. Fletcher, Daniel Ward, Lucia Marucci, Sandra Montes Olivas, Martin Homer |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Cell cycle checkpoint
lcsh:Biotechnology Hippo pathway Cell Crypt Biophysics Wnt pathway BrisSynBio Biology Biochemistry intestinal crypt 03 medical and health sciences 0302 clinical medicine Structural Biology lcsh:TP248.13-248.65 Genetics medicine 030304 developmental biology ComputingMethodologies_COMPUTERGRAPHICS 0303 health sciences Hippo signaling pathway Engineering Mathematics Research Group Systems Biology Bristol BioDesign Institute Wnt signaling pathway Contact inhibition systems biology Cell cycle agent-based modelling Intestinal crypt Computer Science Applications Cell biology Agent-based modelling medicine.anatomical_structure Cytoplasm 030220 oncology & carcinogenesis HIppo pathway Biotechnology Modelling Tissue Dynamics Research Article |
| Zdroj: | Computational and Structural Biotechnology Journal Computational and Structural Biotechnology Journal, Vol 18, Iss, Pp 230-240 (2020) Ward, D, Montes Olivas, S, Fletcher, A, Homer, M & Marucci, L 2020, ' Cross-talk between Hippo and Wnt signalling pathways in intestinal crypts : Insights from an agent-based model ', Computational and Structural Biotechnology Journal, vol. 18, pp. 230-240 . https://doi.org/10.1016/j.csbj.2019.12.015 |
| ISSN: | 2001-0370 |
| Popis: | Graphical abstract Intestinal crypts are responsible for the total cell renewal of the lining of the intestines; this turnover is governed by the interplay between signalling pathways and the cell cycle. The role of Wnt signalling in cell proliferation and differentiation in the intestinal crypt has been extensively studied, with increased signalling found towards the lower regions of the crypt. Recent studies have shown that the Wnt signalling gradient found within the crypt may arise as a result of division-based spreading from a Wnt ‘reservoir’ at the crypt base. The discovery of the Hippo pathway’s involvement in maintaining crypt homeostasis is more recent; a mechanistic understanding of Hippo pathway dynamics, and its possible cross-talk with the Wnt pathway, remains lacking. To explore how the interplay between these pathways may control crypt homeostasis, we extended an ordinary differential equation model of the Wnt signalling pathway to include a phenomenological description of Hippo signalling in single cells, and then coupled it to a cell-based description of cell movement, proliferation and contact inhibition in agent-based simulations. Furthermore, we compared an imposed Wnt gradient with a division-based Wnt gradient model. Our results suggest that Hippo signalling affects the Wnt pathway by reducing the presence of free cytoplasmic β-catenin, causing cell cycle arrest. We also show that a division-based spreading of Wnt can form a Wnt gradient, resulting in proliferative dynamics comparable to imposed-gradient models. Finally, a simulated APC double mutant, with misregulated Wnt and Hippo signalling activity, is predicted to cause monoclonal conversion of the crypt. |
| Databáze: | OpenAIRE |
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