Receptor Noise and Directional Sensing in Eukaryotic Chemotaxis

Rappel, Wouter‐Jan; Levine, Herbert

doi:10.1103/physrevlett.100.228101

Cited by 64 publications

(73 citation statements)

References 16 publications

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“…Our experiments in which the local concentration was restricted to a narrow range show that the CI increases for increasing gradient steepness (Fig 2A). These results are in agreement with recent theoretical investigations of the directional sensing process that predict a sigmoidal dependence of the CI on the gradient steepness (16,27). Our results also indicate that the minimum gradient steepness required for a directional response depends on the local concentration: Cells exposed to a 1.25% gradient do not respond directionally in a 1-to 10-nM concentration range but do respond in a 10-to 30-nM concentration range.…”

Section: Discussionsupporting

confidence: 82%

“…The optimal local concentration for neutrophils in an exponential gradient was also determined to be ∼K d (10) whereas an analysis in which receptors are randomly distributed can reduce the optimal concentration by at most 50% (26). Thus, our experiments, combined with this theoretical analysis, suggest that the processing of the gradient cues inside cells reduces the optimal local concentration for chemotaxis and that this optimal concentration is determined through a convolution of the external (i.e., receptor binding and unbinding) and internal steps (27).…”

Section: Discussionmentioning

confidence: 80%

“…Recently, the role of fluctuations in chemotaxis has received significant attention (15,16,18,20,26,27). Most studies, however, were either purely theoretical or performed under conditions that were difficult to quantify.…”

Section: Discussionmentioning

confidence: 99%

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External and internal constraints on eukaryotic chemotaxis

Fuller¹,

Chen²,

Adler³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Chemotaxis, the chemically guided movement of cells, plays an important role in several biological processes including cancer, wound healing, and embryogenesis. Chemotacting cells are able to sense shallow chemical gradients where the concentration of chemoattractant differs by only a few percent from one side of the cell to the other, over a wide range of local concentrations. Exactly what limits the chemotactic ability of these cells is presently unclear. Here we determine the chemotactic response of Dictyostelium cells to exponential gradients of varying steepness and local concentration of the chemoattractant cAMP. We find that the cells are sensitive to the steepness of the gradient as well as to the local concentration. Using information theory techniques, we derive a formula for the mutual information between the input gradient and the spatial distribution of bound receptors and also compute the mutual information between the input gradient and the motility direction in the experiments. A comparison between these quantities reveals that for shallow gradients, in which the concentration difference between the back and the front of a 10-μm-diameter cell is <5%, and for small local concentrations (<10 nM) the intracellular information loss is insignificant. Thus, external fluctuations due to the finite number of receptors dominate and limit the chemotactic response. For steeper gradients and higher local concentrations, the intracellular information processing is suboptimal and results in a smaller mutual information between the input gradient and the motility direction than would have been predicted from the ligand-receptor binding process.mutual information | noise limits | Dictyostelium | microfluidics C hemotaxis, the motion of cells guided by chemical gradients, plays an important role in a variety of biological processes, including wound healing, embryogenesis, and cancer metastasis. The chemical gradients required for efficient chemotaxis can be very shallow for eukaryotic cells. For example, the rapidly crawling neutrophils of the mammalian immune system and the social amoebae, Dictyostelium discoideum (1-8), are able to sense shallow chemical gradients where the concentration of chemoattractant differs by only a few percent from one side of the cell to the other, over a wide range of local concentrations (9-11).The chemotactic response of these cells can be considered as the outcome from two distinct steps: establishment of spatial differences in the distribution of receptors with bound chemoattractant on the cell's surface (12) and the response to these differences by the signal transduction pathways leading to directed motility (13). The first step is subject to the external fluctuations in chemoattractant binding to the surface receptor. This external noise can be precisely characterized, either through direct numerical simulations (14, 15) or through approximate analytical calculations (16-18). The second step involves a number of pathways that are subject to internal background noise generated ...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 80%

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External and internal constraints on eukaryotic chemotaxis

Fuller¹,

Chen²,

Adler³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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127

168

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“…A number of other studies have also recognized the importance of noise in directional sensing (20)(21)(22)(23)(24). Several of these attempt to estimate the SNR of the input signal, taken to be the difference between the number of bound receptors at the front and at the back of the cell (20,23).…”

Section: Discussionmentioning

confidence: 99%

“…Several recent studies have investigated this issue, by using different approaches, including information theoretical ones (21), general considerations (20,22,23) and 1D caricatures of the cell (24). What has been lacking to date, however, is a treatment of the directional sensing problem that (i) exactly quantifies the fluctuations in the number of bound receptors taking into account the spatial extent of the cell and (ii) couples this noisy signal to a downstream intracellular directional sensing pathway.…”

Section: Uring Eukaryotic Chemotaxis Chemical Gradients Determinementioning

confidence: 99%

Receptor noise limitations on chemotactic sensing

Rappel

Levine

2008

Proc. Natl. Acad. Sci. U.S.A.

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Chemotactic eukaryotic cells are able to detect chemoattractant gradients that are both shallow and have a low background concentration. Under these conditions, the noise in the number of bound receptors can be significant and needs to be taken into account in determining the directional sensing process. Here, we quantify numerically the number of bound receptors on the membrane of a disk-shaped cell by using a numerical Monte Carlo tool. The obtained time traces of the receptor occupancy can be used as inputs for any directional sensing model. We investigate the response of the local excitation global inhibition model and a recently developed balanced inactivation model. We determine a measure for the motility of the cell for each model, based on the relevant output variable, as a function of experimental parameters, resulting in several experimentally testable predictions. Furthermore, we show that these two models behave in a qualitatively different fashion when the background concentration is varied. Thus, to properly characterize the sensitivity of cells to receptor occupancy, it is not sufficient to examine the input signal. Rather, one needs to take into account the response of the second messenger pathway.chemotaxis | motility D uring eukaryotic chemotaxis, chemical gradients determine and guide the crawling motion of cells. Chemotaxis plays a fundamental role in development and in immune responses and is implicated in the spreading of cancer (1-3). The external gradient of the chemoattractant results in an asymmetric distribution of bound receptors on the cell's membrane and the directional sensing process translates this receptor asymmetry into directed cell motion. A number of biochemical components of the directional sensing pathway of several model systems have been determined (4-7) and an array of different mechanisms have been proposed, including Turing-type instability mechanisms (8), phase separation mechanisms (9), bistable mechanisms (10), depletion mechanisms (11, 12), and communication through diffusible inhibitors (13)(14)(15)(16). Despite the recent experimental progress and theoretical efforts, however, the precise mechanisms underlying chemotaxis, in general, and directional sensing, in particular, are poorly understood (17,18).Further complicating the directional sensing problem is the potential role of stochasticity. It has been shown that cells are able to chemotax in very shallow gradients with a large range of background concentrations (19,20). For these shallow gradients the difference in the number of bound receptors at the front and the back of the cell can be as little as 20. Comparing this with the total number of bound receptors, which is of the order of several hundred, leads to the question of noise in directional sensing.Several recent studies have investigated this issue, by using different approaches, including information theoretical ones (21), general considerations (20,22,23) and 1D caricatures of the cell (24). What has been lacking to date, however, is a treatment of...

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Decoding the chemotactic signal

Thomas

Kleist

Volkman

2018

Journal of Leukocyte Biology

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From an individual bacterium to the cells that compose the human immune system, cellular chemotaxis plays a fundamental role in allowing cells to navigate, interpret, and respond to their environments. While many features of cellular chemotaxis are shared among systems as diverse as bacteria and human immune cells, the machinery that guides the migration of these model organisms varies widely. In this article, we review current literature on the diversity of chemoattractant ligands, the cell surface receptors that detect and process chemotactic gradients, and the link between signal recognition and the regulation of cellular machinery that allow for efficient directed cellular movement. These facets of cellular chemotaxis are compared among E. coli, Dictyostelium discoideum, and mammalian neutrophils to derive organizational principles by which diverse cell systems sense and respond to chemotactic gradients to initiate cellular migration.

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Receptor Noise and Directional Sensing in Eukaryotic Chemotaxis

Cited by 64 publications

References 16 publications

External and internal constraints on eukaryotic chemotaxis

External and internal constraints on eukaryotic chemotaxis

Receptor noise limitations on chemotactic sensing

Decoding the chemotactic signal

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