Sloppy and stiff directions in parameter space and the fidelity of meiotic exit in budding yeast

Meiosis ensures the formation of haploid gametes through two rounds of chromosome segregation after one round of DNA replication. How this complex cell cycle process is limited to two and only two divisions is poorly understood. In budding yeast, RNA-binding protein Rim4 forms aggregated fibrils that bind various mRNAs to prevent their translation. At the onset of meiosis II, phosphorylation-mediated degradation of Rim4 and concomitant release of sequestered mRNA has been shown to be important in ensuring fidelity of meiotic exit. Indeed, phase separated condensates consisting of key molecules together with other proteins or RNA are crucial for the spatial and temporal regulation of various cellular processes. We present a cooperative description of Rim4-mRNA association and dissociation kinetics, coupled to a parsimonious model of meiotic termination network based on experimental results for the deletion of key network constituents. As in many examples of cellular regulatory circuits, this leads to a multiparameter model. We explore the sensitivity of the output in a high dimensional parameter space, revealing combinations of parameters to which the functional output is sensitive (“stiff” directions), and a larger subspace in which parameters can vary significantly with less substantial effect (“sloppy” directions). We interpret these results in the context of the fidelity and variability of meiotic exit.