Cells proliferate by means of the mitotic cell cycle, which underlies development, growth and maintenance in all living organisms. While the cell cycle has fascinated biologists for many years, unravelling the mechanisms that drive cell division is far from complete. M-phase entry is a switch-like transition orchestrated by phosphorylation of hundreds of proteins that govern the mechanics of cell division. These “mitotic substrates” are controlled by a cohort of kinases and phosphatases, themselves regulated by two master enzymes: the mitotic kinase Cdk1-Cyclin B (MPF for M-phase Promoting Factor) and its antagonizing phosphatase, PP2A. Since meiotic divisions use the same molecular players than mitosis, oocytes have been used as a historically important model system to study cell division.
Our work is dedicated to the understanding of the control of meiotic divisions by using the Xenopus oocyte as a model system. Oocytes are arrested in prophase of the 1st meiotic division, assimilated to a late G2 arrest. The release from the prophase block of frog oocytes is triggered by progesterone. This steroid induces a rapid decrease of the cAMP concentration and PKA activity, allowing de novo synthesis of Cyclin B1 and Mos kinase from stored mRNAs. These proteins lead to MPF activation, promoting the 1st meiotic division. MPF activity falls during anaphase I, due to partial Cyclin degradation, and rises again leading to entry into meiosis II. The oocyte arrests at metaphase II, because of the stabilization of MPF by Mos.
Our projects focus on several questions:
1. The role of the PKA substrate, Arpp19, in preventing M-phase entry;
2. Activating Cdk1 in meiosis: role of Arpp19 and deciphering the interactome of Cdk1-Cyclin B complexes;
3. Beyond Xenopus meiosis: Arpp19 as a master regulator in other models;
4. The translational control of meiotic divisions.