A review of models of fluctuating protrusion and retraction patterns at the leading edge of motile cells

Abstract

A characteristic feature of motile cells as they undergo a change in motile behavior is the development of fluctuating exploratory motions of the leading edge, driven by actin polymerization. We review quantitative models of these protrusion and retraction phenomena. Theoretical studies have been motivated by advances in experimental and computational methods that allow controlled perturbations, single molecule imaging, and analysis of spatiotemporal correlations in microscopic images. To explain oscillations and waves of the leading edge, most theoretical models propose nonlinear interactions and feedback mechanisms among different components of the actin cytoskeleton system. These mechanisms include curvature-sensing membrane proteins, myosin contraction, and autocatalytic biochemical reaction kinetics. We discuss how the combination of experimental studies with modeling promises to quantify the relative importance of these biochemical and biophysical processes at the leading edge and to evaluate their generality across cell types and extracellular environments. V C 2012 Wiley Periodicals, Inc Key Words: actin, cell motility, lamellipodium dynamics, mathematical modeling, single molecule microscopy Introduction E ukaryotic cell motility is driven by actin protrusions at the leading edge, formation of adhesions, and myosin-driven contraction at the trailing edge. Understanding the function of these three motility components has inspired a huge body of biological, biochemical, and modeling work [Mogilner and Keren, 2009;Pollard and Cooper, 2009;Carlsson, 2010a;Watanabe, 2010]. Prior work has addressed many of the underlying molecular mechanisms of protrusion, adhesion, and retraction, as well as their combined influence in determining cell shape and motion. Many works have also examined the mechanisms of control of cell motility: how cells respond to stimuli in order to reorganize their cytoskeleton and move along a preferred direction [Jilkine and Edelstein-Keshet, 2010].In this review, we focus on a dynamical pattern of motile cells that involves cycles of protrusion-and-retraction (CPAR) of the leading edge. This type of motion consists of back and forth movements of the leading edge over a few microns over a few minutes. It is usually more pronounced as cells change polarization states, for example, during cell spreading or cell stimulation (Fig. 1). CPAR dynamics occur reproducibly in experiments and are easy to quantify as compared to other more complex features of cell shape. Statistical analysis of these repeated motions can provide insight into the regulatory mechanisms of motility. For this reason, in addition to novel experimental work, they have motivated mathematical and computational modeling studies and development of image analysis methods. We discuss some of the conceptual contributions of these quantitative studies to cell motility research and challenges for future feedback between experiment and theory.One of the best examples of CPAR occurs during cell spreading [Dobereiner et al., , 2006Du...

Excitable Signal Transduction Networks in Directed Cell Migration

“…Similar propagating waves or evidence for excitability of signal transduction and cytoskeletal events have been observed in neutrophils (Weiner et al, 2007), mast cells (Wu et al, 2013), fibroblast (Ryan et al, 2012; Case and Waterman, 2011) and other cells (Winans et al, 2016). In some cases, the similar phase relationships among various components has been documented.…”

Modeling Contact Inhibition of Locomotion of Colliding Cells Migrating on Micropatterned Substrates

“…One natural choice would be to develop a more detailed description of the statistics of cell protrusions in neural crest, e.g. including stochastic protrusion and retraction [63] as has been modeled for Dictyostelium [64, 65]. Inclusion of hydrodynamic flow within the cells, as we have previously studied for single cells [31, 41], could potentially be relevant as well, especially if we were to extend our study from collisions in micropatterns to microchannels [66].…”

Actin Migration Driven by Directional Assembly and Disassembly of Membrane-Anchored Actin Filaments

“…Previous work has shown that inhibitors of actin polymerization block their generation and migration (Ruthel and Banker, 1998;Toriyama et al, 2006;Weiner et al, 2007;Bretschneider et al, 2009). However, how actin polymerization mediates the wave-like migration of actin and associated proteins is unknown (Carlsson, 2010a;Ryan et al, 2012;Allard and Mogilner, 2013).…”