The essential role of Cyclin B3 in female meiosis I

Abstract

For the formation of new life by the fusion of egg and sperm it is essential that the resulting organism contains again the same number of chromosomes as the parents9 cells. This is ensured by a special form of cell division, called meiosis. Meiotic divisions halve the number of chromosomes in the germ cells, ensuring a constant number of chromosomes in the next generations. The generation of oocytes starts with DNA replication, resulting in doubled number of chromosomes, followed by two rounds of divisions, each halving the number of chromosomes remaining in the oocyte. During these two meiotic divisions the oocyte arrests two times: The first arrest occurs in prophase of the first meiotic division (prophase I), the second arrest occurs in metaphase of the second meiotic division (metaphase II). While the prophase I arrest is maintained by inhibition of a protein complex consisting of Cyclin B and Cyclin dependent kinase 1 (Cdk1), it is well known that the second arrest is characterized by inhibition of the ubiquitin ligase Anaphase Promoting Complex /Cyclosome (APC/C). If the APC/C becomes active it targets cell cycle regulating proteins for degradation, resulting in release from cell cycle arrest. In metaphase II arrest, the APC/C is inhibited by a direct inhibitor, called XErp1. XErp1 levels are high in metaphase II but it is absent in prophase I. So far, it is unknown, how oocytes distinguish between meiosis I and meiosis II and how inappropriate accumulation of XErp1 in meiosis I is prevented. We addressed this question by analyzing Cyclin B3 as potential regulator of XErp1. Cyclin B3 depletion was previously found to inappropriately arrest oocytes in the first meiotic division. We could show that indeed Cyclin B3 is required for regulation of XErp1 in the first meiotic division and that it does so by mediating phosphorylation on N-terminal sites of XErp1. By this, Cyclin B3 is not only causing subsequent XErp1 degradation, but also preventing it from inhibiting the APC/C.