Molecular and cellular control of oocyte maturation in mammals

The ability to produce a healthy fertile egg is essential for reproduction. Problems associated with the development of eggs are a major cause of infertility and early embryo loss (miscarriage). One of the reasons why eggs are so vulnerable is that they go through a specialised process known as meiosis. This process starts during foetal life and does not finish until after the egg is fertilized; more than 40 years later in some cases. Furthermore, women are born with all the eggs that will be available for her reproductive lifespan; no new eggs can be made. In meiosis the egg stops and starts at different stages but spends most of its life in a so-called ?dormant? state in the ovary. At some point the egg starts to grow increasing in diameter by 5 fold and in volume by about 300 fold to become one of the largest cells in the body (one-tenth of a millimetre across). Through all of this process the egg remains arrested in development and it is not until just before ovulation that the egg continues meiosis and halves the number of chromosomes. This meiotic division is prone to errors and is the single main reason why there is such a dramatic decrease in fertility as women get older, particularly over the age of 40. We are using mouse eggs to try to understand how meiosis works so that we can understand more about how to keep eggs arrested and healthy in the ovary and how they can go through the meiotic division without errors that cause poor quality embryos. Advances in our research are communicated in scientific journals, specialist websites and by press releases to the mainstream media. This way we aim to keep scientists, those with special interest and the public aware of our MRC funded research.

In the UK more than 10% of couples seek medical help to get pregnant. The extent of this problem points to a major problem in the ability to generate high quality oocytes capable of developing into viable embryos. This problem is exacerbated in older mothers because there is a well established exponential increase in the rate of chromosome abnormalities that starts in the mid-late 30s. The overall aim of this research is to investigate the cell biology and physiology that underpins the formation of a healthy fertile oocyte. To tackle this we will address four specific themes:
1. To investigate the role of the anaphase promoting complex (APC) in maintaining physiological meiotic arrest and its impact on long term fertility.
2. To investigate how APC regulation controls oocyte maturation and explain how aberrant APC activity impacts the first meiotic division.
3. To determine the role of cyclin A in meiosis I and whether aberrant control of cyclin A stability contributes to metaphase I arrest.
4. To understand how the oocyte deals with DNA damage and whether the G2 DNA damage checkpoint contributes to age-related increases in aneuploidy.

These themes address aspects of the control of meiosis in mammalian oocytes. We will use oocytes from fertile mice, mice of advanced maternal age and in some cases conditional transgenic mice in which genes of interest have been deleted specifically from the oocyte. Human immature oocytes will be used in an effort to apply our advances to the human system as rapidly as possible. We will use microinjection, oocyte culture, confocal and conventional imaging techniques to explore how oocytes remain arrested in meiosis and how the transition through the first meiotic division is controlled. The experiments are expected to yield results that will benefit the treatment of infertility and reproductive medicine more widely.