External and internal constraints on eukaryotic chemotaxis

Abstract

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 ...

High fidelity information processing in folic acid chemotaxis ofDictyosteliumamoebae

“…It is currently believed that Dictyostelium measure chemical gradients directly by monitoring the distribution of the occupied chemoattractant receptors. These cells can detect concentration differences as low as a few per cent across their cell bodies [3][4][5][6][7][8] and it is currently an open question what exactly limits this process. Previously, the receptor -ligand binding fluctuations were suggested as the limiting factor, which remains a possibility because a single excited receptor may amplify the signal by activating multiple G-proteins [9][10][11].…”

“…Fuller et al [4] recently exploited this information-theoretic framework, where a cell in a static gradient was modelled as N receptors arranged in a circle, each in chemical equilibrium with the local chemoattractant concentration, described by a dissociation constant K d .…”

The influence of receptor positioning on chemotactic information

“…A powerful approach for analysing such problems is to consider the optimal statistical inference that an ideal observer would perform (Andrews and Iglesias, 2007;Mortimer et al, 2009;Fuller et al, 2010;Hu et al, 2010Hu et al, , 2011aMortimer et al, 2011). This involves combining available information with prior assumptions.…”

How receptor diffusion influences gradient sensing

“…In particular, we consider the limits to the information available to a cell for decision-making, without addressing the mechanisms by which a cell could access that information via downstream signalling mechanisms. Many such previous models of gradient sensing have assumed, for the sake of simplicity, that receptors are immobile [6,9,10,20,21]. In these models, each receptor has a fixed probability of binding with ligand molecules which depends on the local ligand concentration at the receptor's position.…”