Cellular asymmetry and individuality in directional sensing

Abstract

It is generally assumed that single cells in an isogenic population, when exposed to identical environments, exhibit the same behavior. However, it is becoming increasingly clear that, even in a genetically identical population, cellular behavior can vary significantly among cells. Here we explore this variability in the gradientsensing response of Dictyostelium cells when exposed to repeated spatiotemporal pulses of chemoattractant. Our experiments show the response of a single cell to be highly reproducible from pulse to pulse. In contrast, a large variability in the response direction and magnitude is observed from cell to cell, even when different cells are exposed to the same pulse. First, these results indicate that the gradient-sensing network has inherent asymmetries that can significantly impact the ability of cells to faithfully sense the direction of extracellular signals (cellular asymmetry). Second, we find that the magnitude of this asymmetry varies greatly among cells. Some cells are able to accurately follow the direction of an extracellular stimulus, whereas, in other cells, the intracellular asymmetry dominates, resulting in a polarization axis that is independent of the direction of the extracellular cue (cellular individuality). We integrate these experimental findings into a model that treats the effective signal a cell detects as the product of the extracellular signal and the asymmetric intracellular signal. With this model we successfully predict the population response. This cellular individuality and asymmetry might fundamentally limit the fidelity of signal detection; in contrast, however, it might be beneficial by diversifying phenotypes in isogenic populations.T he low number of molecules involved in biological systems can lead to large stochastic effects and population heterogeneity even within a genetically identical population (1-3). For example, the swimming behavior of Escherichia coli cells varies greatly from cell to cell (4), and recent studies start to link this variability in swimming behavior to concentration fluctuations in regulatory proteins (5-7). It is an open question whether a similar variability can be observed in eukaryotic chemotactic cells, such as the slime mold Dictyostelium discoideum, which has the exquisite ability to sense and respond to shallow gradients of chemoattractants. In these spatially sensitive systems, signaling errors might be introduced in two different ways. First, the concentrations of intracellular signaling components might vary from cell to cell; second, spatial inhomogeneities or asymmetries in the cellular distributions of molecules might influence the ability of cells to sense slight spatial differences in the extracellular environment.To explore this question, we employ a quantitative approach to systematically study directional sensing in single Dictyostelium cells. Recent experiments have demonstrated that an extracellular signal induces spatial localization of several signaling proteins along the plasma membrane (8-12). The localiz...

Bayes-Optimal Chemotaxis

“…From the perspective of statistical decision theory, we can identify the polarization of a cell with an asymmetric prior distribution for the gradient direction. This is also consistent with experiments in which D. discoideum cells were transiently stimulated by growing them in a medium containing caged cAMP, then using a short laser pulse to uncage the cAMP (Samadani, Mettetal, & van Oudenaarden, 2006). In this study, Dictyostelium cells were observed to show more or less 'bias' towards some apparently random prior direction.…”

High fidelity information processing in folic acid chemotaxis ofDictyosteliumamoebae

“…The results here and in [4,11] confirmed that the external noise dominates for both chemoattractants in low concentration range. This is in contrast to the conclusion reached in the Supplementary Information of Samadani & Mettetal [31], SI possibly caused by using single-pulse temporal gradients, as opposed to defined static gradients used here and in [4].…”

“…In the intermediate range where I ext ) I tot , the internal noise dominates. We note that it has been shown [31] that there is always a fraction of cell population which does not respond to gradients and polarizes in random directions, independent of the external cAMP gradient. Since in our experiments we only have static gradients, we could not separately identify these cells and they had to be included in the data analysis.…”

Cell memory and adaptation in chemotaxis

“…The results presented suggest that the cell is able to integrate extrinsic (chemoattractants) and intrinsic (memory/polarity) information (16). How this is accomplished is unclear, but one possibility is directly through the G protein-coupled receptor used to bind cAMP.…”