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Quantitative dynamic analysis of homologous chromosome segregation and its coordination with the asymmetric meiotic division in live mouse oocytes

Final Report Summary - OOCYTE ASYMMETRY (Quantitative dynamic analysis of homologous chromosome segregation and its coordination with the asymmetric meiotic division in live mouse oocytes)

In most animal species, sexual reproduction requires the fusion of two haploid gametes: the spermatozoon and the oocytes. In mammalian oocytes, the process that ensures the formation of these highly specialised cells is called meiotic maturation. In the neonatal ovary, oocytes are naturally arrested at prophase I of the first meiotic division during the growth phase which is characterised by an intensive transcription and storage of maternal factors. Maternal factors are essential for maturation and early development. The meiotic arrest is maintained until puberty when the luteinising hormone (LH) surge stimulates the maturation. During this period, the oocyte undergoes two cellular divisions without an intermediate phase of DNA replication. The first meiotic division results in the metaphase II-arrest of the oocyte (MII), in which chromosomes and the second meiotic spindle remain in a stable state for hours waiting for fertilisation. This division is a unique type of chromosome segregation for two main reasons. First, it segregates homologous chromosome pairs rather than sister chromatids, as occurs in mitosis and in the second meiotic division. Second, the chromosomes are segregated only when the meiotic spindle has been positioned at the cortex of the oocyte. This division is extremely asymmetric in order to preserve the stored nutrients of the oocyte for the early embryo. Errors in segregation of chromosomes during the first meiotic division can result in the generation of aneuploid embryos with severe birth defects such as Down syndrome. 90 % of human trisomies have a maternal origin of aneuploidy with a link established with aging. Chromosome missegregations during meiosis-I are also responsible for pregnancy loss. As in mitosis, chromosome missegregation during meiotic division is prevented by the spindle assembly checkpoint that monitors chromosome biorientation and their attachment to microtubules. However, the spatio-temporal regulation of homologous chromosome segregation remains poorly understood. The aim of my project, in Dr Ellenberg?s group, was to characterise new cellular and molecular mechanisms that coordinate accurate chromosome segregation during the first meiotic division in mouse oocytes. I characterised new mechanisms that regulate the timing of chromosome segregation during the first meiotic division of mammalian oocytes, by using high resolution live imaging confocal microscopy and gene knock down method.

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