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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM097479-03
Application #
8448293
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Maas, Stefan
Project Start
2011-04-18
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$486,004
Indirect Cost
$179,995
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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