Living systems use information about external conditions and information retrieved from their genomes to determine their future actions. The centrality of information in determining future behavior defines a key difference between biological systems and other complex physical systems. In metazoans, decision making in response to regulatory molecules in the extracellular environment is critical for development of the adult organism from the zygote and for maintenance of the adult soma. We therefore wish to understand how cells convert extracellular signals into quantitative measurements and how cells transmit and operate on this information. Our continuing studies of a prototypic cell signaling system, the Saccharomyces cerevisiae pheromone response system, have provided insights into these questions. Findings have come from experiments on single cells using engineered protein reporters and image cytometry to quantify molecular events in system operation. Although fruitful, the simplification required for these studies neglects a key aspect of metazoan signaling: the extracellular regulatory molecules that orchestrate many key cell decisions are distributed in gradients. Gradients of regulatory ligand molecules are ubiquitous in vertebrates. The ability of vertebrate cells to correctly determine ligand concentration in gradients (for fate decisions), to correctly determine the ligand gradient vector (for polarity decisions), and to limit cell-to-cell variation in these determinations (for coherent responses by cell populations) is critical throughout development and adult life. Like vertebrate signaling systems, the prototype yeast system enables cells to read concentration and polarity vector of a ligand gradient. We will use the yeast system to understand the biophysical and molecular mechanisms cells use to determine concentration and polarity vector in gradients and that limit cell-to-cell-variation in these determinations. This work has been made possible by greatly increased single cell experimental abilities and recent development of microfludic devices allowing experimental observation of large numbers of cells in well-controlled gradients. During the next five years, for cells in gradients, we will elucidate biophysical and molecular mechanisms that bring about the speed and accuracy of concentration determination, that enable quick and accurate gradient determination, and that make the responses of cell populations more coherent by restricting cell-to-cell variation in these determinations. A mechanism-based quantitative understanding of how cells make these determinations and limit cell-to-cell variation in them would advance basic knowledge and would likely suggest paths to manipulate particular quantitative behaviors in order to achieve therapeutic ends.
This work will help us understand how cells read amounts and directions of signal molecules in gradients, and how groups of cells respond coherently by reading these the same way. In multicellular animals, including humans, these processes are critical for development of the adult from the fertilized egg, for maintenance of the adult body (as cells in tissues die and new ones replace them), and during development of cancers (particularly solid tumors). Understanding will guide future basic research and may suggest paths for therapeutic interventions.
|Altszyler, Edgar; Ventura, Alejandra C; Colman-Lerner, Alejandro et al. (2017) Ultrasensitivity in signaling cascades revisited: Linking local and global ultrasensitivity estimations. PLoS One 12:e0180083|
|Sands, Bryan; Brent, Roger (2016) Overview of post Cohen-Boyer methods for single segment cloning and for multisegment DNA assembly. Curr Protoc Mol Biol 113:3.26.1-3.26.20|
|Andrews, Steven S; Peria, William J; Yu, Richard C et al. (2016) Push-Pull and Feedback Mechanisms Can Align Signaling System Outputs with Inputs. Cell Syst 3:444-455.e2|
|Andrews, Steven S; Rutherford, Suzannah (2016) A Method and On-Line Tool for Maximum Likelihood Calibration of Immunoblots and Other Measurements That Are Quantified in Batches. PLoS One 11:e0149575|
|Bush, Alan; Vasen, Gustavo; Constantinou, Andreas et al. (2016) Yeast GPCR signaling reflects the fraction of occupied receptors, not the number. Mol Syst Biol 12:898|
|Mendenhall, Alexander; Driscoll, Monica; Brent, Roger (2016) Using measures of single-cell physiology and physiological state to understand organismic aging. Aging Cell 15:4-13|
|Cao, Ruofan; Jenkins, Patrick; Peria, William et al. (2016) Phasor plotting with frequency-domain flow cytometry. Opt Express 24:14596-607|
|Emiola, Akintunde; Andrews, Steven S; Heller, Carolin et al. (2016) Crosstalk between the lipopolysaccharide and phospholipid pathways during outer membrane biogenesis in Escherichia coli. Proc Natl Acad Sci U S A 113:3108-13|
|Doncic, Andreas; Atay, Oguzhan; Valk, Ervin et al. (2015) Compartmentalization of a bistable switch enables memory to cross a feedback-driven transition. Cell 160:1182-95|
|Mendenhall, Alexander R; Tedesco, Patricia M; Sands, Bryan et al. (2015) Single Cell Quantification of Reporter Gene Expression in Live Adult Caenorhabditis elegans Reveals Reproducible Cell-Specific Expression Patterns and Underlying Biological Variation. PLoS One 10:e0124289|
Showing the most recent 10 out of 26 publications