Grant: Operating Grant

At fertilisation a new individual is created by the fusion of the sperm and the egg, each of which contributes half of the genetic material (chromosomes) for the offspring. However, for reasons that are very poorly understood, the development of the egg is error-prone, such that unfertilised eggs frequently possess the wrong number of chromosomes. This is particularly the case as women get older. These chromosomally abnormal ('aneuploid') eggs are the cause of developmental conditions such as Down's, are a leading cause of miscarriage, and are the leading reason for age-related infertility. We will investigate the cause of aneuploidy in eggs, particularly focussing on the spindle, the part of the cell responsible for ensuring that chromosomes are correctly divided between cells (called chromosome segregation) during the final cell division which occurs as part of egg development. Using state-of-the-art microscopy we will compare spindles in eggs from old mice and young mice, to determine precisely why the spindle in the developing egg from older mothers is more prone to chromosome segregation errors. Our preliminary data suggest that the kinesin-13s family of proteins, which are important for correct chromosomes segregation in many cells, may be defective in old eggs. We will test the role of kinesin-13s in developing eggs, and establish which of these proteins are the most important for preventing chromosome segregation-errors. Moreover, in collaboration with clinical colleagues, we will perform some of the first such studies in human eggs, and determine whether kinesin-13s are important for preventing aneuploidy. Our experiments will provide key information as to why developing eggs are likely to mis-segregate chromosomes, particularly in older mothers, and thus will help explain why pregnancy establishment becomes more difficult as women become older.