Systems-level modeling of meiotic entry, commitment, progression and exit

Upon nitrogen starvation, Schizosaccharomyces pombe (fission yeast) exits the mitotic cell cycle and becomes irreversibly committed to the completion of the meiosis program. In meiosis, DNA replication (S-phase) is followed by two successive rounds of cell divisions (Meiosis I and Meiosis II) without intermediate interphase. In this work, we developed a comprehensive model of the entire meiotic cell cycle, which couples exit from mitosis to meiotic commitment and progression under nitrogen starvation. This network was assembled from several experimental observations in the literature for meiotic cell divisions and exit. The core of the regulatory network is the regulation of cyclin-dependent kinase (Cdk) 1 and anaphase-promoting complex or cyclosome (APC/C) by meiosis-specific factors. The network was translated into a set of ordinary differential equations to simulate the dynamics of meiotic progression. We also performed one and two-parameter bifurcations to study the role of different feedback loops in meiosis. The model accounts for about 60 experimental situations including single and multiple mutations and demonstrates the control strategy involving multiple feedback loops to yield two successive division cycles. The model serves as a key tool for experimentalists to perform in silico mutations and test the hypothesis.