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Regulated cell-to-cell variation in a cell-fate decision system

An Erratum to this article was published on 26 January 2006

Abstract

Here we studied the quantitative behaviour and cell-to-cell variability of a prototypical eukaryotic cell-fate decision system, the mating pheromone response pathway in yeast. We dissected and measured sources of variation in system output, analysing thousands of individual, genetically identical cells. Only a small proportion of total cell-to-cell variation is caused by random fluctuations in gene transcription and translation during the response (‘expression noise’). Instead, variation is dominated by differences in the capacity of individual cells to transmit signals through the pathway (‘pathway capacity’) and to express proteins from genes (‘expression capacity’). Cells with high expression capacity express proteins at a higher rate and increase in volume more rapidly. Our results identify two mechanisms that regulate cell-to-cell variation in pathway capacity. First, the MAP kinase Fus3 suppresses variation at high pheromone levels, while the MAP kinase Kss1 enhances variation at low pheromone levels. Second, pathway capacity and expression capacity are negatively correlated, suggesting a compensatory mechanism that allows cells to respond more precisely to pheromone in the presence of a large variation in expression capacity.

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Figure 1: Quantifying sources of cell-to-cell variation.
Figure 2: Quantification of system output in single cells during α-factor response.
Figure 3: Cell-to-cell variation is dominated by initial differences between cells.
Figure 4: The cell-cycle kinase Cdc28 causes a large part of the variation in α-factor system output.
Figure 5: Genetic control of cell-to-cell variation in pathway subsystem output η2(P).

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Acknowledgements

We are grateful to D. Pincus for his help with the MAPK phosphorylation measurements and to L. Lok, K. Benjamin, I. Burbulis and R. Yu for discussions and comments on the manuscript. Work was under the ‘Alpha Project’ at the Center for Genomic Experimentation and Computation, an NIH Center of Excellence in Genomic Science. The Alpha Project is supported by a grant from the National Human Genome Research Institute to R.B. Author Contributions A.C.-L. and A.G. conceived the framework, developed the experimental methods, performed most of the experiments and analysed the results. R.B. provided input regarding problem choice, experimentation and interpretation. A.C.-L., A.G. and R.B. wrote the paper and stand as guarantors of its findings. T.C. made most of the plasmid and yeast strains. E.S. made some plasmids and yeast strains, and some of the measurements in Fig. 2. C.G.P. made the observation that Fus3 regulates pathway variation and collaborated in interpreting its biological implications. O.R. and A.C.-L. made the observation that activated Fus3/Kss1 ratios are α-factor-dependent. D.E. suggested analysis of the stochastic fluctuations in the system and helped with describing the framework.

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Correspondence to Alejandro Colman-Lerner.

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Colman-Lerner, A., Gordon, A., Serra, E. et al. Regulated cell-to-cell variation in a cell-fate decision system. Nature 437, 699–706 (2005). https://doi.org/10.1038/nature03998

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