Distinct Interactions Select and Maintain a Specific Cell Fate

Abstract

The ability to specify and maintain discrete cell fates is essential for development. However, the dynamics underlying selection and stability of distinct cell types remains poorly understood. Here, we provide a quantitative single-cell analysis of commitment dynamics during the mating-mitosis switch in budding yeast. Commitment to division corresponds precisely to activating the G1 cyclin positive feedback loop in competition with the cyclin inhibitor Far1. Cyclin-dependent phosphorylation and inhibition of the mating pathway scaffold Ste5 is required to ensure exclusive expression of the mitotic transcriptional program after cell cycle commitment. Failure to commit exclusively results in coexpression of both cell cycle and pheromone-induced genes, and a morphologically-mixed inviable cell fate. Thus, specification and maintenance of a cellular state are performed by distinct interactions, which is likely a consequence of disparate reaction rates and may be a general feature of the interlinked regulatory networks responsible for selecting cell fates.

Mathematical modeling reveals the mechanisms of feedforward regulation in cell fate decisions in budding yeast

“…Apparently, during the competition between the two groups of proteins, once one cell fate dominates, the proteins representing the other cell fate are suppressed completely. These results agree well with experimental data [13].We further investigate the relationship between the time of pheromone addition and Whi5P activation, as shown in Figure S3. Our calculation for the curve of cell fate decision indicates that there is a sharp transition point at 3 min (i.e., the critical addition time is 3 min.…”

“…The G1 checkpoint of a cycling cell is termed the Start point [17,18]. The mechanisms of feedforward regulation in cell fate decisionsPrevious studies have identified the fractions of Whi5 protein that are removed from the nucleus as the main indicator for the status of the G1 checkpoint trigger [13]. In the recent work of our group, the Start point is quantified mathematically by the largest derivative in the dose-response curve, which can be obtained from the relationship between the activation of Whi5 (i.e., the proportion of Whi5 that has been exported from the nucleus at 30 min) and the pheromone application time [7].…”

“…In the recent work of our group, the Start point is quantified mathematically by the largest derivative in the dose-response curve, which can be obtained from the relationship between the activation of Whi5 (i.e., the proportion of Whi5 that has been exported from the nucleus at 30 min) and the pheromone application time [7]. The pheromone application time at the Start point is considered the critical addition time, and the fraction of Whi5 at the Start point is termed the Whi5-threshold.The critical fractions of Whi5 for cycling cells obtained from the statistical analysis of biological data and the mathematical definition are both approximately equal to 0.5 [7,13]. Therefore, in this study, we still use our original definition [7] to characterize Start point.…”

Evolution of networks and sequences in eukaryotic cell cycle control

“…This structure clearly has many favourable dynamical features that we have documented in recent work in the yeast system: cell size control [16], positive feedback-driven coherent cell cycle entry [18,19] and irreversibility [20,44]. Many of these features have been attributed to the animal system as well [40,42].…”

“…The transition point (i.e. Start) between these two steps corresponds to cell cycle commitment arising from the abrupt feedback-driven increase in G1 cyclin transcription rate [19,20].…”