The nuclear-cytoplasmic ratio controls the cell cycle period in compartmentalized frog egg extract

Each proliferating cell replicates its DNA and internal components before distributing this material evenly to its daughters. Although the regulation of cyclin-dependent kinases (Cdks) that dictate orderly cell cycle progression is well characterized, how the subcellular localization of the cell cycle machinery contributes to timing is not well understood. We investigated the influence of the nucleus by reconstituting cell cycle oscillations in droplets of frog egg extract in the absence or presence of a nuclear compartment and monitoring dynamics by time-lapse microscopy. We found that the cell cycle time increased in the presence of nuclei, which grew larger with each cell cycle. The correlation between increasing nuclear volume and a longer cell cycle period was maintained across extracts and nuclei from various Xenopus species and persisted upon inhibition of DNA replication or transcription. However, inhibition of nuclear import or the kinase Wee1 impacted the relationship between the nuclear-cytoplasmic ratio and the cell cycle period. To conceptually capture these experimental observations, we developed a computational model that incorporates cell cycle oscillations, nuclear-cytoplasmic compartmentalization, and periodic nuclear envelope breakdown and reformation. Altogether, our results support the major role of the nuclear compartment in setting the pace of the cell cycle and provide an explanation for the increase in cell cycle length observed at the midblastula transition when cells become smaller and the nuclear-cytoplasmic ratio increases.