Last modified: 2014-03-31
Abstract
Motile cells like neutrophils have the aptitude to polarize, i.e. the ability to rearrange multiple proteins and lipids in response to chemical or mechanical cues. This rearrangement leads to a symmetry break in the cell, defining a distinct front and back, which determines the direction of ensuing actin filament alignment. A variety of mathematical models of neutrophil polarization have been suggested over the last decade. As diverse as they are, all of them have in common that polarization arises solely through biochemical interactions in signaling pathways.
However, recent experimental studies have begun to reveal the necessity of an interplay between chemical and mechanical signaling for the establishment and maintenance of polarity in neutrophils. In accordance to these studies we propose a mathematical model of neutrophil polarization based on chemical mediated local activation and mechanical mediated global inhibition. In particular, the model incorporates membrane associated Rho GTPase cycling as an activator of diffusion-driven cytosolic downstream effectors that initiate actin polymerization. Due to the actin-driven membrane protrusion at the leading edge membrane tension increases globally, which suppresses GTPase activity. The mathematical formulation of this model leads to a 1-dimensional spatio-temporal system, whose consistency and ability of pattern formation under a wide range of kinetic functions is proved. Furthermore, the response of the system to various stimuli is considered. The simulated dynamic behavior of this system not only reproduces Rac activity in a good agreement to experimental data, but also depicts the subsequent alignment of the actin cytoskeleton from a symmetric resting to a Rac gradient-facing state.
Our goal is to present a minimal and yet holistic scenario that discloses the interplay of GTPase activity, actin dynamics and membrane tension in order to explain generation and maintenance of neutrophil polarity.