Modeling robustness tradeoffs in yeast cell polarization induced by spatial gradients.
Bottom Line:
Increasing the positive feedback gain resulted in better amplification, but also produced multiple steady-states and hysteresis that prevented the tracking of directional changes of the gradient.Feedforward/feedback coincidence detection in the positive feedback loop and multi-stage amplification both improved tracking with only a modest loss of amplification.Surprisingly, we found that introducing lateral surface diffusion increased the robustness of polarization and collapsed the multiple steady-states to a single steady-state at the cost of a reduction in polarization.
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PubMed Central - PubMed
Affiliation: Department of Mathematics, Center for Mathematical and Computational Biology, Center for Complex Biological Systems, University of California Irvine, Irvine, California, United States of America.
ABSTRACT
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Cells localize (polarize) internal components to specific locations in response to external signals such as spatial gradients. For example, yeast cells form a mating projection toward the source of mating pheromone. There are specific challenges associated with cell polarization including amplification of shallow external gradients of ligand to produce steep internal gradients of protein components (e.g. localized distribution), response over a broad range of ligand concentrations, and tracking of moving signal sources. In this work, we investigated the tradeoffs among these performance objectives using a generic model that captures the basic spatial dynamics of polarization in yeast cells, which are small. We varied the positive feedback, cooperativity, and diffusion coefficients in the model to explore the nature of this tradeoff. Increasing the positive feedback gain resulted in better amplification, but also produced multiple steady-states and hysteresis that prevented the tracking of directional changes of the gradient. Feedforward/feedback coincidence detection in the positive feedback loop and multi-stage amplification both improved tracking with only a modest loss of amplification. Surprisingly, we found that introducing lateral surface diffusion increased the robustness of polarization and collapsed the multiple steady-states to a single steady-state at the cost of a reduction in polarization. Finally, in a more mechanistic model of yeast cell polarization, a surface diffusion coefficient between 0.01 and 0.001 µm(2)/s produced the best polarization performance, and this range is close to the measured value. The model also showed good gradient-sensitivity and dynamic range. This research is significant because it provides an in-depth analysis of the performance tradeoffs that confront biological systems that sense and respond to chemical spatial gradients, proposes strategies for balancing this tradeoff, highlights the critical role of lateral diffusion of proteins in the membrane on the robustness of polarization, and furnishes a framework for future spatial models of yeast cell polarization. |
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Mentions: For didactic purposes, we explored a version of the model in which we let γ = γ′(1/(1+(βu)−q)), γ′ = 1 (see Section 2.5 for further description); the essential results did not depend on the particular model. For k1 = 0, there was a single solution, and we obtained an expression in which a is a function of the input-dependent Hill cooperativity term. For h = 1 (k1 = 10 s−1), only one value of b satisfied the integral constraint, and the resulting quadratic equation in a possessed only one positive root. Thus, there was at most a single steady-state, which is shown in Fig. 3. For h = 2, there were multiple feasible values of b resulting in a family of root curves. The resulting polynomials were cubic, and depending on the parameter values, there could be one or three real roots, which could be stable or unstable. In Figure 3 (h = 2) for a given bs, we observed a lower stable root and an upper stable root and an overlapping region containing two stable roots and one unstable root. One forms a solution by connecting the stable points along the x-axis in a manner that satisfies the integral constraint, crossing between the lower and upper root curves in the overlapping region (blue lines). There were multiple solutions for each root curve given that one can cross between the lower and upper roots multiple times, but typically we were most interested in the solution with the highest polarization value, which is what is drawn in blue. The envelope of solutions represents the highest polarized solutions for each feasible b, and thus does not represent all possible solutions. |
View Article: PubMed Central - PubMed
Affiliation: Department of Mathematics, Center for Mathematical and Computational Biology, Center for Complex Biological Systems, University of California Irvine, Irvine, California, United States of America.