Negative Feedback Enhances Robustness in the Yeast Polarity Establishment Circuit

• Published in: Cell Vol. 149; no. 2; pp. 322 - 333
• Main Authors: Howell, Audrey S., Jin, Meng, Wu, Chi-Fang, Zyla, Trevin R., Elston, Timothy C., Lew, Daniel J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.04.2012
• Subjects: cdc42 GTP-Binding Protein, Saccharomyces cerevisiae - metabolism; Cell Polarity; Circuits; Competition; Computed tomography; Feedback; Feedback, Physiological; Guanine Nucleotide Exchange Factors - metabolism; image analysis; Kinetics; Mathematical models; Models, Biological; Polarity; Polarization; prediction; Saccharomyces cerevisiae; Saccharomyces cerevisiae - cytology; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; yeasts
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2012.03.012

Many cells undergo symmetry-breaking polarization toward a randomly oriented “front” in the absence of spatial cues. In budding yeast, such polarization involves a positive feedback loop that enables amplification of stochastically arising clusters of polarity factors. Previous mathematical modeling suggested that, if more than one cluster were amplified, the clusters would compete for limiting resources and the largest would “win,” explaining why yeast cells always make one and only one bud. Here, using imaging with improved spatiotemporal resolution, we show the transient coexistence of multiple clusters during polarity establishment, as predicted by the model. Unexpectedly, we also find that initial polarity factor clustering is oscillatory, revealing the presence of a negative feedback loop that disperses the factors. Mathematical modeling predicts that negative feedback would confer robustness to the polarity circuit and make the kinetics of competition between polarity factor clusters relatively insensitive to polarity factor concentration. These predictions are confirmed experimentally. [Display omitted] ► Imaging at high spatiotemporal resolution shows symmetry breaking process in yeast ► Polarity factors polarize in an oscillatory manner indicative of negative feedback ► Modeling shows that negative feedback increases robustness of polarization ► Negative feedback promotes rapid competition between clusters of polarity factors High-resolution filming of yeast polarization during bud formation, combined with modeling, shows that both positive and negative feedback loops make the polarization process robust and rapid, ensuring the selection of a single bud site.