The most dramatic moment in the life of a cell is the time of cell division to give rise to two daughter cells. The groups of K. Wassmann (Group MOM, Developmental Biology, IBPS, Paris)1 and S. Keeney (MSKCC, New York) have found that a M-phase cyclin with hitherto unknown function, namely cyclin B3, is essential for proper execution of meiotic divisions in oocytes. Mice without cyclin B3 are viable, but females are sterile. Hence, this cyclin is not required for mitosis or male fertility, but only to generate oocytes for fertilization. Our results furthermore indicate that cyclin B3's role in oocyte meiosis is conserved throughout evolution. These results were published in the Journal of Cell Biology2.
Two different types of cell division exist, mitosis and meiosis. Mitosis takes place in the tissues that constitute our body, whereas meiosis is a succession of two specialized cell divisions to generate gametes harbouring only half the genetic complement of the parental germ cell. On a molecular level, progression through cell division is regulated by Cdk1 associated with M-phase cyclins. For mitotic cell division to take place, replicated chromosomes have to condense, attach to a structure named the mitotic spindle, and align at the so-named metaphase plate. When all chromosomes are correctly attached and aligned, the spindle tears chromosomes apart to the opposite poles to form two new daughter cells. Cells exit mitosis and a new cell cycle can start. But o generate haploid gametes in meiosis, germ cells undergo two differing cell divisions with distinct patterns of chromosome segregation and without intervening S-phase. Thereby four daughter cells that harbour only half the chromosome count are generated. Upon fusion of the male and female gamete, the original chromosome count is reconstituted in the offspring.
Entry and progression through mitosis and meiosis depend on the rise and fall of cyclin-dependent kinase 1 (Cdk) activity. To be active, Cdk1 needs to be associated with one of several cyclins. In the mouse, cyclin B1 is thought to be the essential cyclin to regulate key steps of cell division. Whether different M-phase cyclins have non-redundant roles in mitosis and meiosis, was unknown. Using mice that have been genetically invalidated for the gene encoding cyclin B3, we show here that cyclin B3 has a specific function only in oocytes. Without cyclin B3, oocytes cannot finish the first meiotic division, because degradation of key factors that is required for chromosome segregation, is not taking place. Our data point to cyclin B3 promoting timely activation of the E3 ubiquitin ligase named Anaphase Promoting Complex (APC), specifically in the first meiotic division. This failure to correctly activate the APC perturbs progression into the second meiotic division and results in sterility. Other M-phase cyclins cannot substitute for cyclin B3 in female meiosis. Strikingly, cyclin B3 from other species such as frog and even drosophila can rescue mouse oocytes devoid of cyclin B3, indicating conservation of cyclin B3's role in oocytes throughout evolution. Our work highlights the specificities of cell cycle regulation in oocytes. We speculate that due to the huge size of the oocyte and due to the fact that two cell divisions have to be executed without interphase, cyclin B3 is necessary for fine-tuning the APC.
For more information, see the short note published on the CNRS website and in "En direct des labos"