Hersen P, McClean M, Ramanathan S. [Dynamic analysis of cell signalling: the example of the Saccharomyces cerevisiae osmotic response]. Med Sci (Paris). 2008;24 (12) :1020-2.
Hersen P, McClean MN, Mahadevan L, Ramanathan S. Signal processing by the HOG MAP kinase pathway. Proc Natl Acad Sci U S A. 2008;105 (20) :7165-70.Abstract
Signaling pathways relay information about changes in the external environment so that cells can respond appropriately. How much information a pathway can carry depends on its bandwidth. We designed a microfluidic device to reliably change the environment of single cells over a range of frequencies. Using this device, we measured the bandwidth of the Saccharomyces cerevisiae signaling pathway that responds to high osmolarity. This prototypical pathway, the HOG pathway, is shown to act as a low-pass filter, integrating the signal when it changes rapidly and following it faithfully when it changes more slowly. We study the dependence of the pathway's bandwidth on its architecture. We measure previously unknown bounds on all of the in vivo reaction rates acting in this pathway. We find that the two-component Ssk1 branch of this pathway is capable of fast signal integration, whereas the kinase Ste11 branch is not. Our experimental techniques can be applied to other signaling pathways, allowing the measurement of their in vivo kinetics and the quantification of their information capacity.
McClean MN, Mody A, Broach JR, Ramanathan S. Cross-talk and decision making in MAP kinase pathways. Nat Genet. 2007;39 (3) :409-14.Abstract
Cells must respond specifically to different environmental stimuli in order to survive. The signal transduction pathways involved in sensing these stimuli often share the same or homologous proteins. Despite potential cross-wiring, cells show specificity of response. We show, through modeling, that the physiological response of such pathways exposed to simultaneous and temporally ordered inputs can demonstrate system-level mechanisms by which pathways achieve specificity. We apply these results to the hyperosmolar and pheromone mitogen-activated protein (MAP) kinase pathways in the yeast Saccharomyces cerevisiae. These two pathways specifically sense osmolar and pheromone signals, despite sharing a MAPKKK, Ste11, and having homologous MAPKs (Fus3 and Hog1). We show that in a single cell, the pathways are bistable over a range of inputs, and the cell responds to only one stimulus even when exposed to both. Our results imply that these pathways achieve specificity by filtering out spurious cross-talk through mutual inhibition. The variability between cells allows for heterogeneity of the decisions.
Nachman I, Regev A, Ramanathan S. Dissecting timing variability in yeast meiosis. Cell. 2007;131 (3) :544-56.Abstract
Cell-to-cell variability in the timing of cell-fate changes can be advantageous for a population of single-celled organisms growing in a fluctuating environment. We study timing variability during meiosis in Saccharomyces cerevisiae, initiated upon nutritional starvation. We use time-lapse fluorescence microscopy to measure the timing of meiotic events in single cells and find that the duration of meiosis is highly variable between cells. This variability is concentrated between the beginning of starvation and the onset of early meiosis genes. Cell-cycle variability and nutritional history have little effect on this timing variability. Rather, variation in the production rate of the meiotic master regulator Ime1 and its gradual increase over time govern this variability, and cell size effects are channeled through Ime1. These results tie phenotypic variability with expression dynamics of a transcriptional regulator and provide a general framework for the study of temporal developmental processes.
Hallatschek O, Hersen P, Ramanathan S, Nelson DR. Genetic drift at expanding frontiers promotes gene segregation. Proc Natl Acad Sci U S A. 2007;104 (50) :19926-30.Abstract
Competition between random genetic drift and natural selection play a central role in evolution: Whereas nonbeneficial mutations often prevail in small populations by chance, mutations that sweep through large populations typically confer a selective advantage. Here, however, we observe chance effects during range expansions that dramatically alter the gene pool even in large microbial populations. Initially well mixed populations of two fluorescently labeled strains of Escherichia coli develop well defined, sector-like regions with fractal boundaries in expanding colonies. The formation of these regions is driven by random fluctuations that originate in a thin band of pioneers at the expanding frontier. A comparison of bacterial and yeast colonies (Saccharomyces cerevisiae) suggests that this large-scale genetic sectoring is a generic phenomenon that may provide a detectable footprint of past range expansions.
Ramanathan S, Detwiler PB, Sengupta AM, Shraiman BI. G-protein-coupled enzyme cascades have intrinsic properties that improve signal localization and fidelity. Biophys J. 2005;88 (5) :3063-71.Abstract
G-protein-coupled enzyme cascades are used by eukaryotic cells to detect external signals and transduce them into intracellular messages that contain biological information relevant to the cell's function. Since G-protein-coupled receptors that are designed to detect different kinds of external signals can generate the same kind of intracellular response, effective signaling requires that there are mechanisms to increase signal specificity and fidelity. Here we examine the kinetic equations for the initial three stages in a generic G-protein-coupled cascade and show that the physical properties of the transduction pathway result in two intrinsic features that benefit signaling. 1), The response to a single activated receptor is naturally confined to a localized spatial domain, which could improve signal specificity by reducing cross talk. 2), The peak of the response generated by such a signaling domain is limited. This saturation effect reduces trial-to-trial variability and increases signaling fidelity by limiting the response to receptors that remain active for longer than average. We suggest that this mechanism for reducing response fluctuations may be a contributing factor in making the single photon responses of vertebrate retinal rods so remarkably reproducible.
Ramanathan S, Swain PS. Tracing the sources of cellular variation. Dev Cell. 2005;9 (5) :576-8.Abstract
As the adage says, variety is the spice of life, and despite our best attempts, cells, even those with the same genome, never seem to behave the same. By combining mathematical and experimental analyses, Colman-Lerner and colleagues propose, in a recent issue of Nature, a method to delicately unravel the sources of this variation. Applying their technique to the pheromone response in budding yeast, they show that much of the observed variation originates from cell cycle effects and is dependent on levels of pathway input.
Mach P, Kerbage C, Ramanathan S, Windeler RS, Eggleton BJ, Rogers JA. Influence of scattering on transmission through long-period fiber gratings and tunable microstructure fibers. Appl Opt. 2002;41 (33) :7018-24.Abstract
Controlled optical scattering within or around an optical fiber provides a potentially useful mean for adjusting its transmission characteristic. This approach can complement conventional methods based on the establishment of well-defined variations in the index of refraction of the core or the cladding of the fiber. We describe the use of a highly scattering submonolayer of nanoparticles deposited onto the fiber surface for adjusting the resonance wavelength, depth, and width of an in-fiber long-period grating filter. We also introduce a polymer-dispersed liquid-crystal material that has a thermally tunable scattering cross section and can be incorporated into the channels of a microstructure optical fiber; this system may provide the means for a fiber-based scattering switch.