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MAPK-mediated bimodal gene expression and adaptive gradient sensing in yeast

Nature volume 446, pages 46–51 (2007)Cite this article

Abstract

The mating pathway in Saccharomyces cerevisiae has been the focus of considerable research effort, yet many quantitative aspects of its regulation still remain unknown. Using an integrated approach involving experiments in microfluidic chips and computational modelling, we studied gene expression and phenotypic changes associated with the mating response under well-defined pheromone gradients. Here we report a combination of switch-like and graded pathway responses leading to stochastic phenotype determination in a specific range of pheromone concentrations. Furthermore, we show that these responses are critically dependent on mitogen-activated protein kinase (MAPK)-mediated regulation of the activity of the pheromone-response-specific transcription factor, Ste12, as well as on the autoregulatory feedback of Ste12. In particular, both the switch-like characteristics and sensitivity of gene expression in shmooing cells to pheromone concentration were significantly diminished in cells lacking Kss1, one of the MAP kinases activated in the mating pathway. In addition, the dynamic range of gradient sensing of Kss1-deficient cells was reduced compared with wild type. We thus provide unsuspected functional significance for this kinase in regulation of the mating response.

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Figure 1: Pheromone dose–response analysis using a microfluidic experimental setup.
Figure 2: Quantification of Fus1 protein and gene expression.
Figure 3: Computational modelling of transcriptional regulation in the pheromone response.
Figure 4: Role of Kss1 in regulating the pheromone response.
Figure 5: Quantification of pheromone gradient sensing.

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Acknowledgements

The authors would like to thank M. Piel from A. Murray’s laboratory (Harvard) for the initial suggestion of the possible importance of Kss1 in controlling bimodality of pheromone response. They also want to thank P. Sternberg, J. Bruck, M. Peter, A. Colman-Lerner, J. Boeke, L. Bardwell and S. Quake for intellectual and material support of the study. This work was supported by NIH and NSF grants.

Author Contributions S.P., A.G. and A.L. conceived the framework of and wrote the paper, and A.L. oversaw the complete project. A.G., K.C., S.P. and A.L. conceptualized the microfluidic device design and the experimental setup, and K.C. and A.G. fabricated the devices. S.P., P.A.I. and A.L. were involved in the mathematical model setup. Z.H., S.P. and A.L. designed the yeast strains used in the study. S.P. performed the experiments, analysis of results and mathematical model simulations.

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Authors and Affiliations

  1. Department of Biomedical Engineering and Whitaker Institute of Biomedical Engineering, and,

    Saurabh Paliwal, Pablo A. Iglesias, Zoe Hilioti & Andre Levchenko

  2. Department of Electrical Engineering and Computer Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA,

    Pablo A. Iglesias

  3. Department of Physics, University of California, San Diego, La Jolla, California 92093, USA,

    Kyle Campbell & Alex Groisman

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  1. Saurabh Paliwal
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Correspondence to Alex Groisman or Andre Levchenko.

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This file contains Supplementary Methods, Supplementary Discussions, Supplementary Table 1, Supplementary Figures S1-S17 with Legends and additional references. A list of the contents of this file is included on the first page. (PDF 3236 kb)

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Paliwal, S., Iglesias, P., Campbell, K. et al. MAPK-mediated bimodal gene expression and adaptive gradient sensing in yeast. Nature 446, 46–51 (2007). https://doi.org/10.1038/nature05561

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