Mad2 prevents aneuploidy and premature proteolysis of cyclin B and securin during meiosis I in mouse oocytes

Homer HA, McDougall A, Levasseur M, Yallop K, Murdoch AP, Herbert M
Genes Dev. 2005 Jan 15;19(2):202-7

During the development of the human egg, the chromosomes in the egg-producing cell (or oocyte) undergo two consecutive divisions during a process called meiosis in order to produce a mature egg containing half the normal number of chromosomes. When the egg so produced is combined with the sperm’s genetic material upon fertilization, a full compliment of chromosomes is reconstituted in the resulting embryo. Meiosis is achieved through a complex sequence of events that involves the formation of a scaffolding-like structure of microtubules in the oocyte called the spindle. Correct execution of these events is an essential pre-requisite for faithful partitioning of the chromosomes during meiosis, a critical event if the embryo is to develop correctly and the baby is to thrive [Cell Cycle 2005 May;4:650–653; Nature Cell Biology 2003 Nov;5(11):1023-5].

In stark contrast to meiosis in sperm precursors, the first of the two consecutive meiotic divisions in human oocytes (or female meiosis I) is highly prone to division errors. These female meiosis I errors are a major cause of miscarriage, IVF failure and birth defects, such as mental retardation. Studies from non-oocyte cell-types have demonstrated that the fidelity of chromosome segregation is improved when the biochemical events, which drive the process of chromosome segregation, occur at a controlled rate. One of these crucial biochemical events is the timely destruction of two proteins (securin and cyclin B) which have recently been shown to be important in mammalian oocytes during meiosis I [Nature Cell Biology 2003 Nov;5(11):1023-5]. In non-oocyte cell-types, a proof-reading network known as the Spindle Assembly Checkpoint (SAC) is important for scheduling the proper timing of chromosome segregation. SAC proteins, including Mad2, delay destruction of securin and cyclin B and consequently chromosome separation until they are properly anchored to the spindle. Although the indispensability of the SAC to the maintenance of chromosome constitution in virtually all mammalian cell-types other than oocytes has been known for a decade and half, the requirement for an SAC during meiosis I in mammalian oocytes was unknown.

In this study, the researchers used complex genetic techniques to deplete levels of Mad2 in oocytes in order to investigate the role of this protein in meiosis I. They found that Mad2 is critical for accurate division of the chromosomes and for the regulation of other proteins that control meiosis, such as cyclin B and securin. Depletion of Mad2 levels resulted in a staggering increase in inaccurate chromosome division –and a shorter duration of meiosis.

Conditions resulting from inaccurate chromosome division, such as Down’s syndrome, occur more commonly in older women. Studies such as this support the appealing hypothesis that a decline in the function of the SAC may contribute to the higher incidence of babies with Down’s syndrome born to older women. The authors’ postulate that this may be due to reduced levels of SAC proteins such as Mad2 in the oocyte with advancing maternal age [Cell Cycle 2005 May;4:650–653]. In keeping with this, oocytes from older women appear to have reduced levels of Mad2-generating templates (or mRNA) when compared with oocytes from younger women. It is hoped that greater understanding of the mechanisms involved in early meiosis in oocytes may, in the future, help to reduce the incidence of congenital abnormalities in our children and improve the success rates of reproductive therapies such as IVF.

27 Sussex Place
Regent's Park
London NW1 4SP

Tel: 020 7772 6400
Fax: 020 7724 7725
wellbeingofwomen@rcog.org.uk

Registered Charity No: 239281

---

Follow us / Join us:

• 
• 
• 

---