Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling

Mol Syst Biol. 2018 Apr 4;14(4):e7390. doi: 10.15252/msb.20167390.


Populations of isogenic cells often respond coherently to signals, despite differences in protein abundance and cell state. Previously, we uncovered processes in the Saccharomyces cerevisiae pheromone response system (PRS) that reduced cell-to-cell variability in signal strength and cellular response. Here, we screened 1,141 non-essential genes to identify 50 "variability genes". Most had distinct, separable effects on strength and variability of the PRS, defining these quantities as genetically distinct "axes" of system behavior. Three genes affected cytoplasmic microtubule function: BIM1, GIM2, and GIM4 We used genetic and chemical perturbations to show that, without microtubules, PRS output is reduced but variability is unaffected, while, when microtubules are present but their function is perturbed, output is sometimes lowered, but its variability is always high. The increased variability caused by microtubule perturbations required the PRS MAP kinase Fus3 and a process at or upstream of Ste5, the membrane-localized scaffold to which Fus3 must bind to be activated. Visualization of Ste5 localization dynamics demonstrated that perturbing microtubules destabilized Ste5 at the membrane signaling site. The fact that such microtubule perturbations cause aberrant fate and polarity decisions in mammals suggests that microtubule-dependent signal stabilization might also operate throughout metazoans.

Keywords: MAP kinase; cell‐to‐cell variability; genetic screen; microtubules; noise.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Cell Cycle Proteins / genetics
  • MAP Kinase Signaling System / genetics*
  • Microtubule Proteins / genetics*
  • Microtubules / genetics*
  • Microtubules / metabolism
  • Mitogen-Activated Protein Kinases / genetics
  • Pheromones / genetics
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics
  • Signal Transduction / genetics
  • Single-Cell Analysis*


  • Adaptor Proteins, Signal Transducing
  • BIM1 protein, S cerevisiae
  • Cell Cycle Proteins
  • Microtubule Proteins
  • Pheromones
  • STE5 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • FUS3 protein, S cerevisiae
  • Mitogen-Activated Protein Kinases

Associated data

  • Dryad/10.5061/dryad.67bc0