How mammalian eggs stop and start their meiotic cell cycle
Mammalian eggs spend months, years or even decades in the case of humans, arrested in their cell cycle before completing their meiotic divisions. Completion of meiosis ensures that they are haploid, and once fertilized regain two copies of every chromosome. How is this arrest achieved? It’s long been known that key to this arrest is maintaining low levels of the kinase CDK1. High CDK1 activity induces eggs to resume meiosis, and CDK1 phosphorylation was thought to be the only essential mechanism of maintaining arrest. However, CDK1 needs its regulatory partner cyclin B1 for activity and we established that the egg has a second equally important arrest mechanism involving cyclin B1 degradation. We found that low cyclin B1 levels were necessary to maintain arrest and this is achieved by its degradation through the anaphase-promoting complex/cyclosome (APC/C), activated by an accessory protein cdh1. APC/Ccdh1 also degrades cyclin B1 in adult cells but there it is during exit from mitosis rather than during entry. thus the egg has used a well-known mitotic protein complex for a specialised meiotic function. Once the egg has committed itself to meiosis it must undergo two divisions to become haploid. To get out of the first division and enter the second, the egg must decrease CDK1 activity. Normally in mitosis this is done by degradation of its regulatory partner cyclin B1. However, we found that eggs neutralise CDK1 activity by binding separase, a protease normally associated with cleaving cohesion. Blocking the physical interaction of separase with CDK1, blocked the ability of the eggs to complete their meiotic division.
Reis A, Chang HY, Levasseur M and Jones KT 2006. APCcdh1 activity in mouse oocytes prevents entry into the first meiotic division. Nature Cell Biology 8, 539-40.
Gorr IH, Reis A, Boos D, Wuhr M, Madgwick S, Jones KT and Stemmann O (2006). Essential CDK1-inhibitory role for separase during meiosis I in vertebrate oocytes. Nature Cell Biology 8, 1035-7.
