Factors responsible for restart of meiotic cycle

The Hawley Lab has described the dual actions of these two proteins as the “Sleeping Beauty Kiss” that awakens the long-dormant egg, allowing for production of a mature oocyte ready for fertilization. The findings appear in the Dec. 4, 2007 issue of PLoS Biology.

The long period of dormancy that interrupts the process that parses out the correct number of chromosomes is characteristic of female meiosis. The cells that will become oocytes in human females develop during fetal development and begin the actual process of meiosis before birth, but the oocytes remain in a suspended state until the female reaches sexual maturity.

Extended periods of dormancy may last many years in organisms like humans, but shorter periods of meiotic arrest can be found in simpler, more easily studied species like the fruit fly — the model used by the Hawley Lab in this work. In the fruit fly, oocyte development is arrested for 3-4 days at exactly the same point in meiosis as in humans.

The long period of meiotic arrest has mystified biologists for over a century because it raises the question of just how the “sleeping” oocyte is reawakened. The Hawley Lab addressed this question and determined that there are two molecular solutions at play: the controlled expression of a protein that restarts the cell cycle and the inactivation of an inhibitory protein that had previously prevented the restart of meiosis.

“This work led us to the conclusion that the restart of the meiotic cycle in Drosophila depends on two mechanisms,” said Youbin Xiang, Ph.D., Research Specialist II and first author on the paper. “First, the controlled expression of an ‘activator,’ known as Polo kinase, and second, the presence of a regulatory protein called Matrimony, which binds to and physically inactivates Polo.”

It takes the oocyte several days to build-up enough Polo kinase to properly restart meiosis, and the newly made Polo must remain inactive until a proper level has been reached. Matrimony serves exactly this function by inhibiting Polo kinase. However, at the proper point in oocyte development, Matrimony is destroyed — releasing a sudden surge of active Polo kinase. It is this precisely timed release of active Polo kinase that restarts meiosis.

“Matrimony is the first known protein inhibitor of Polo kinase,” explains R. Scott Hawley, Ph.D., Investigator, and senior author on the paper. “The excess of Matrimony prior to the time of normal meiotic restart keeps Polo inactive. However, the destruction of Matrimony at the appropriate time releases active Polo, permitting a properly controlled restart of meiotic progression.”

The long-term implications of this work for human health and biology lie in a better understanding of how eggs are matured and released, knowledge that will have profound implications for treating infertility. Additionally, Polo kinase is strongly expressed in many types of tumor cells, so identifying a specific inhibitor for this protein may aid in the development of improved drugs for treating cancer.-Stowers Institute for Medical Research