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Excitable behavior in amoeboid chemotaxis

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Chemotaxis, the directed motion of cells in response to chemical gradients, is a fundamental process. Eukaryotic cells detect spatial differences in chemoattractant receptor occupancy with high precision and use these differences to bias the location of actin‐rich protrusions to guide their movement. Research into chemotaxis has benefitted greatly from a systems biology approach that combines novel experimental and computational tools to pose and test hypotheses. Recently, one such hypothesis has been postulated proposing that chemotaxis in eukaryotic cells is mediated by locally biasing the activity of an underlying excitable system. The excitable system hypothesis can account for a number of cellular behaviors related to chemotaxis, including the stochastic nature of the movement of unstimulated cells, the directional bias imposed by chemoattractant gradients, and the observed spatial and temporal distribution of signaling and cytoskeleton proteins. WIREs Syst Biol Med 2013, 5:631–642. doi: 10.1002/wsbm.1230 This article is categorized under: Models of Systems Properties and Processes > Cellular Models Biological Mechanisms > Cell Signaling Analytical and Computational Methods > Dynamical Methods

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Excitable behavior in chemotactic, eukaryotic cells. (a) Total internal reflection fluorescent (TIRF) microscopy images of neutrophil‐like HL‐60 cells expressing Hem‐1‐YFP (a subunit of the Scar‐WAVE compound) continuously exposed to chemoattractant. The outwardly propagating waves eventually develop into a polarized accumulation of Hem‐1 at the leading edge (arrow at 112 seconds). The last two panels overlay successive Hem‐1 distributions. (Reprinted with permission from Ref 11. Copyright 2007 CC‐BY) (b) TIRF images of Dictyostelium cells expressing GFP‐coronin and mRFP‐LimEΔ (a marker for newly polymerized actin). Bottom panels, which plot the fluorescence intensity in the direction of the arrow, show the wave front propagating. Scale bar is 5 µm. (Reprinted with permission from Ref . Copyright 2009 Biophysical Society) (c) Accumulation of GFP‐tagged Hspc‐300 (the Dictyostelium homolog of Hem‐1) in response to a sudden stimulation (at 25 seconds) of chemoattractant. The lower panel shows the average intensity plotted over time, with its large peak followed by a slower, second phase. (d) Simulations of excitable behavior in both unstimulated and stimulated cells. (c and d: Reprinted with permission from Ref . Copyright 2010 National Academy of Sciences USA)
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Response to chemoattractant gradients. (a) Response of a latrunculin‐treated Dictyostelium cell to a needle containing cy3‐cAMP (red). The immobile cell forms a crescent of GFP‐tagged PH‐CRAC in the direction of highest concentration. (Reprinted with permission from Ref . Copyright 2004 National Academy of Sciences USA) (b, c) Overlays of a Dictyostelium cell chemotaxing to a cAMP‐filled micropipette whose location (marked by the dot) is changed in the time between the two panels. The reorientation of the cell to the change in gradient, which is in the form of a gradual ‘u‐turn’ is seen in the overlay of the cell outlines in panel c. Scale bar is 20 µm. (Reprinted with permission from Ref . Copyright 2007 Nature Publishing Group) (d) Reorientation of a Dictyostelium cell by a sufficiently strong change in gradient. Here, the pipette is first moved to the back which stops cytoplasmic flow at which point applying the needle to the side leads to the emergence of multiple pseudopodia. Scale bar is 10 µm. (Reprinted with permission from Ref . Copyright 1982 Elsevier Inc.) (e) Simulation showing the reorientation of a cell in response to a change in the direction of the chemoattractant gradient. (Reprinted with permission from Ref 34. Copyright 2011 CC‐BY)
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Response to spatially uniform stimuli. Translocation of CRAC‐GFP in Dictyostelium cells in response to a short pulse (blue) and continuous (green) stimulation. Scale bar is 10 µm. (Reprinted with permission from Ref . Copyright 2007 American Chemical Society)
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Motility of unstimulated cells. (a) Three 10‐h trajectories of Dictyostelium cells moving in the absence of external stimuli. (Reprinted with permission from Ref 25. Copyright 2008 CC‐BY) (b) Confocal images showing typical extensions of pseudopods in unstimulated Dictyostelium cells. Images are at 8 seconds intervals. In a Y‐split, the existing pseudopod splits in two, of which one is eventually retracted. In a one‐way‐split, a new protrusion is made at the base of an existing pseudopod. De novo pseudopods are those that appear where no recent pseudopod activity has been observed. The outlines below show the direction of the growing pseudopod superimposed on the outline of the earliest image. (c) A 14‐min trajectory of a moving cell with the colored arrows depicting the direction of the different types of pseudopodia. (b and c: reprinted with permission from Ref 26. Copyright 2009 CC‐BY) (d) Pseudopod splits observed in a microfluidic chamber (left) and simulations of an excitable system driving cell protrusions (right). The cell outlines are approximately 2 (left) and 2.5 (right) seconds apart. (Reprinted from Ref 27. Coprright 2009 CC‐BY)
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Dynamical description of excitable behavior. (a) Schematic of an activator (X)‐inhibitor (Y) system, a common framework for studying excitable systems. The system has an autocatalytic positive feedback loop and a negative feedback loop through the inhibitor. (b) Phase‐plane description of the dynamics of the excitable system. The intersection of the two nullclines (lines for which the level of one component remains constant) denotes the equilibrium, which is dynamically stable. In the absence of perturbations, the system remains there (labeled ‘a’). A sufficiently large disturbance leads to a large trajectory in phase‐space (b–c to d–e) before returning to the equilibrium. (c) Trajectories of the activator (green) and inhibitor (red) as a function of time. Note the sub‐basal excursion in the level of the activator, (d–e) which marks the refractory period of the excitable system. (d) Cartoon illustrating how an excitable activator‐inhibitor system can give rise to propagating waves. The positive feedback loop means that functional (shaded green circles) activator molecules recruit other activator molecules (open green circles), thus propagating. They also activate inhibitor molecules (shaded red squares) which turn off the activity. (Reprinted with permission from Ref . Copyright 2012 Elsevier Inc.)
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Biological Mechanisms > Cell Signaling
Analytical and Computational Methods > Dynamical Methods
Models of Systems Properties and Processes > Cellular Models

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