# Spatial distribution of cytoskeleton-mediated feedback controls cell polarization: A computational study

## TL;DR

This study uses computational models to explore how feedback mechanisms in the cytoskeleton help cells maintain direction and structure, with implications for development and disease.

## Contribution

The paper introduces a novel mechanism involving dynamic partitioning of back molecules to enhance polarization efficiency in cell polarity.

## Key findings

- Local and global inhibition mechanisms both stabilize the leading edge and prevent multipolarity.
- Global inhibition is more robust for polarization than local inhibition under varying conditions.
- A new mechanism involving back molecule partitioning improves polarization efficiency.

## Abstract

In the social amoeba Dictyostelium, cell motility is regulated through a signal transduction excitable network that interfaces with the cytoskeleton to control actin polymerization patterns. In turn, the cytoskeleton influences the signaling machinery via several feedback loops, but the nature and function of this feedback remain poorly understood. In this study, we use computational models to discern the essential role of complementary positive and negative feedback loops in polarizing cells. We contrast two potential mechanisms for the negative feedback: local inhibition and global inhibition. Our results indicate that both mechanisms can stabilize the leading edge and inhibit actin polymerization in other sites, preventing multipolarity. While some experimental perturbations align more closely with the local inhibition model, statistical analyses reveal its limited polarization potential within a wide excitability range. Conversely, global inhibition more effectively suppresses secondary and tertiary leading-edge formation, making it a more robust polarization mechanism. This raises an intriguing question: if local inhibition better replicates experimental observations but is less effective for polarization than local excitation and global inhibition, could there be a supplementary mechanism enhancing its polarization potential? To address this, we propose a novel mechanism involving the dynamic partitioning of back molecules which enhances communication between the front and back of the cell and can be leveraged by local feedback interactions between the cytoskeleton and signal transduction to improve polarization efficiency.

Cells use a network of signaling molecules to move and organize themselves, creating distinct front and back regions. Although we know that the cell’s structure influences these signals, the details of how they work together are not fully understood. In this study, we used computational models to study how feedback mechanisms help cells maintain this polarity. We first looked at two types of negative feedback: local feedback, where signals inhibit activity near the site of activity, and global feedback, where inhibition spreads throughout the entire cell. Our simulations showed that both types can stabilize the front of the cell and prevent it from developing multiple leading edges. However, while local feedback closely matched experimental results, it was less effective in maintaining direction under varying conditions. Global feedback proved to be more reliable in preventing the formation of additional leading edges. To address this, we introduced a new idea involving the release and diffusion of molecules, which enhances feedback and improves how well the cell can maintain its direction. Understanding how cells polarize in this way has important implications, such as improving our knowledge of development processes and disease progression.