Microtubule dynamics and age-related aneuploidy in mammalian oocytes

受精时，精子和卵子融合产生一个新的个体，每个精子和卵子为后代贡献一半的遗传物质（染色体）。然而，由于人们知之甚少的原因，卵子的发育容易出错，例如未受精的卵子经常拥有错误的染色体数量。随着女性年龄的增长，情况尤其如此。这些染色体异常（“非整倍体”）卵子是导致发育条件，如唐氏症，是流产的主要原因在这个项目中，我们将研究卵子非整倍体的原因，特别是关注纺锤体，在卵子发育的最后一次细胞分裂中，负责确保染色体在细胞之间正确分裂（称为染色体分离）的细胞部分。我们使用国家的最先进的显微镜检查不同功能的纺锤体功能。我们将比较老年小鼠和年轻小鼠卵子中的纺锤体，以精确确定老年小鼠发育中的卵子中纺锤体的不同之处，这使得它更容易发生染色体分离错误。我们的初步数据与一种称为驱动蛋白-13的蛋白质家族的想法一致，该蛋白质家族可能在确保染色体正确分离方面特别重要，并且在老年卵子中可能有缺陷。我们将使用各种方法直接测试驱动蛋白-13在卵子发育中的作用，并确定哪些蛋白质对防止染色体分离错误最重要。特别是，我们将为老卵提供额外的驱动蛋白-13，以直接防止染色体错误分离。这些实验是第一次尝试防止卵子中与年龄相关的染色体错误分离。我们将与临床同事合作，确定纺锤体操作是否也可以防止人类卵子中的错误。我们的实验将提供关键信息，说明为什么发育中的卵子可能会错误分离染色体，特别是在年长的母亲中，并可能提供原理证明，染色体分离错误，否则会导致疾病，可以通过操纵纺锤体来预防。

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 which 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 (unwanted pregnancy loss), and are the leading reason for age-related infertility.In this project 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. We use state-of-the-art microscopy to examine different features of spindle function. We will be comparing spindles in eggs from old mice and young mice, to determine precisely what is different about the spindle in the developing egg from older mothers, which makes it more prone to chromosome segregation errors.Our preliminary data are consistent with the idea that a family of proteins called Kinesin-13s may be particularly important in making sure chromosomes are segregated correctly, and may be defective in old eggs. We will directly test the role of kinesin-13s in developing eggs using a variety of approaches, and establish which of these proteins are the most important for preventing chromosome segregation-errors. In particular, we will provide old eggs with extra kinesin-13s in a direct attempt to prevent chromosome mis-segregation. These experiments are the first to attempt to prevent age-related chromosome mis-segregation in eggs. In collaboration with clinical colleagues, we will determine whether spindle manipulations can also prevent errors in human eggs.Our experiments will provide key information as to why developing eggs are likely to mis-segregate chromosomes, particularly in older mothers, and may provide proof-of-principle that chromosome segregation errors which would otherwise cause disorders can be prevented by manipulating the spindle.