Establishment of a robust single axis of cell polarity by coupling multiple positive feedback loops

• Published in: Nature communications Vol. 4; no. 1; p. 1807
• Main Authors: Freisinger, Tina, Klünder, Ben, Johnson, Jared, Müller, Nikola, Pichler, Garwin, Beck, Gisela, Costanzo, Michael, Boone, Charles, Cerione, Richard A., Frey, Erwin, Wedlich-Söldner, Roland
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.05.2013; Nature Publishing Group; Nature Pub. Group
• Subjects: 631/80/85; 631/80/86; Actins - metabolism; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; cdc42 GTP-Binding Protein, Saccharomyces cerevisiae - metabolism; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Polarity - drug effects; Chromosome Segregation - drug effects; Computer Simulation; DNA, Fungal - metabolism; Feedback, Physiological - drug effects; Fluorescence Resonance Energy Transfer; Green Fluorescent Proteins - metabolism; Guanine Nucleotide Dissociation Inhibitors - metabolism; Guanosine Triphosphate - metabolism; Humanities and Social Sciences; Hydrolysis - drug effects; Models, Biological; multidisciplinary; Mutation - genetics; Reproducibility of Results; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - growth & development; Saccharomyces cerevisiae - metabolism; Science; Science (multidisciplinary); Stochastic Processes; Thiazolidines - pharmacology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2795

Establishment of cell polarity—or symmetry breaking—relies on local accumulation of polarity regulators. Although simple positive feedback is sufficient to drive symmetry breaking, it is highly sensitive to stochastic fluctuations typical for living cells. Here, by integrating mathematical modelling with quantitative experimental validations, we show that in the yeast Saccharomyces cerevisiae a combination of actin- and guanine nucleotide dissociation inhibitor-dependent recycling of the central polarity regulator Cdc42 is needed to establish robust cell polarity at a single site during yeast budding. The guanine nucleotide dissociation inhibitor pathway consistently generates a single-polarization site, but requires Cdc42 to cycle rapidly between its active and inactive form, and is therefore sensitive to perturbations of the GTPase cycle. Conversely, actin-mediated recycling of Cdc42 induces robust symmetry breaking but cannot restrict polarization to a single site. Our results demonstrate how cells optimize symmetry breaking through coupling between multiple feedback loops. A positive feedback loop which results in localized accumulation of the small GTPase Cdc42 generates cell polarity in budding yeast; however, such loops are inherently susceptible to noise. Here the authors demonstrate how two pathways that mediate Cdc42 recycling work together to ensure the robustness of symmetry breaking.