Goals and results

Exploration of the spatio-temporal dynamics of signaling proteins are relevant to understand how signaling pathways influence cell-biological processes. The Wnt/β-catenin signaling pathway is involved in ReNcell VM cell differentiation. Analysis of the pathway’s signaling proteins via quantitative Western-blots, reveals oscillating protein expression, especially of nuclear β-catenin. Due to their commitment to the cell cycle, ReNcell VM cells start asynchronously to differentiate, which may be the reason for the observed oscillations. Guided by these findings, a stochastic, spatial model of the Wnt/β-catenin pathway in a cell population is developed to verify the previous hypothesis. The model is built in the imperative π-calculus since it is particularly well-suited for modeling spatial distributions in cell populations. The model incorporates cell compartments (cytosol and nucleus), β-catenin shuttling between compartments, a negative Axin feedback loop and cell communication. Simulation results suggest an influence of the cell cycle on nuclear β-catenin dynamics at a multi-cell level, see Figure, and also new promising experimental set-ups.

Interdisciplinarity

On the computer science side, this project showed the usefulness of the imperative π-calculus for the stochastic and spatial modeling of biochemical systems. Moreover, the model denotes for the first time that reactions following Michaelis-Menten kinetics could be implemented in a π-calculus-based approach. Being able to consider abstract reactions with kinetics different to mass action is a crucial feature regarding the practicability of modeling languages in this field. On the biology side, the first stochastic and spatial model of the Wnt/β-catenin pathway in a neural cell population could be developed providing valuable insights into the interplay of the cell cycle and the Wnt/β-catenin signaling in ReNcell VM cells.