Résumé
Frog egg extracts allowed the discovery of the maturation promoting factor (MPF) in the 70s and opened the way to mechanistic studies, emphasizing the role of cyclins and cyclin dependent kinases (CDKs) in orchestrating cell cycle events. Mathematical modeling conciliated irreversible progression of the cell cycle with dynamical systems concepts such as bistability of the MPF. Fifty years since this discovery one would expect that everything about cell cycle mechanisms is known, both on the experimental and theoretical sides. Until recently, it was believed that accumulation of Cyclin B during the G2 stage leads to a tipping point where the inactive CDK1 becomes unstable and spontaneously releases the inhibitory phosphorylation. This traditional picture is challenged by our recent results (Vigneron et al, Dev Cell 2018) showing that Cyclin B alone is not sufficient to push the system over a tipping point. In the case of mitosis, another complex Cyclin A – CDK1 plays the role of a trigger and can push the Cyclin B – CDK1 inactive state over a tipping point. Only when this trigger acts, the Cyclin B – CDK1 complex can play its role of driver of mitotic events. The full mitotic entry wiring also includes the polo-like kinase Plx1, the kinases Aurora A, Greatwall, the phosphatase PP2A-B55, the activator Bora and the inhibitors Arpp19 and ENSA. We applied this methodology also to meiosis. Like for mitosis, the results allowed us to correct the state of the art. The two meiotic cell divisions are controlled by the activity of CDK1 but Cyclin B alone cannot trigger the transitions. Furthermore, it is known that Cyclin A expression is very low in meiosis which asks for a new candidate for the trigger. We have identified a trigger and tested the novel biochemical wiring using a similar combination of experiments and mathematical modeling. Interestingly, our mathematical model shows that the meiotic entry is deterministic for high concentration of the trigger and stochastic when this concentration is low. To apprehend the complex spatio-temporal dynamics of the MPF activation in the oocyte, one can draw an analogy to vapor-liquid first order phase transitions. In the stochastic regime, the oocyte behaves like a superheated fluid. Waves of MPF activation nucleate spontaneously and propagate by auto-catalysis in the cytoplasm. The nucleation process depends on the properties of intrinsic and extrinsic biochemical noise, being bolstered by temporal and spatial correlation of the noise. The pattern of MPF activation coarsens by diffusion controlled processes. These theoretical findings have implications for the understanding of the meiotic cleavage timing and progression of maturation. The trigger is important for reliable meiotic entry, whereas MPF activation waves could coordinate the maturation processes, independently or coupled to surface contraction waves.