Award Title: Maintaining Genetic and Chromosomal Stability in the Mammalian Germline
Funder: Medical Research Council

Abstract: Genetic mutations and chromosomal aneuploidies that arise during germ cell development and meiosis can cause embryonic lethality, miscarriage and genetic disease in the next generation. Aneuploidies such as trisomy 21, which causes Down syndrome, are relatively common in human conceptions, and typically originate during the meiotic divisions of female oocytes. A number of risk factors, including meiotic recombination frequency, distribution of meiotic recombination sites, and maternal age have been identified for oocyte aneuploidy. Furthermore, data from mouse models suggests that age-dependent loss of chromosome cohesion is associated with age-dependent increases in meiotic segregation errors in post-natal oocytes. However, the fundamental mechanisms underlying these processes in mammalian meiosis are not completely understood. This research programme will investigate mechanisms regulating meiotic recombination in mammals, and mechanisms impacting on the maintenance of chromosome cohesion in post-natal mammalian oocytes. We have previously identified components of the ubiquitin-proteasome system as regulators of meiotic recombination frequency in mice. Genetically modified mice carrying mutations in these components of the ubiquitin-proteasome system have reduced meiotic recombination frequencies and defects in pairing homologous chromosomes during meiosis that can cause chromosome segregation errors. However, we do not know how the ubiquitin-proteasome system regulates the early stages of recombination that are defective in these mutants. We will therefore use genetically modified mouse models to investigate how these enzymes influence the machinery that initiates meiotic recombination, and whether recombination in particular regions of the genome are more sensitive to these ubiquitin-proteasome system components. We will also investigate how meiotic chromosomes are organised in mouse spermatocytes and oocytes, and study how meiotic chromosome organisation impacts on the frequency and distribution of meiotic recombination in mice. The second part of this research programme will investigate a novel pathway that we have identified operating in mouse oocytes which helps prevent loss of chromosome cohesion, meiotic chromosome mis-segregation and aneuploidy in post-natal mouse oocytes. This pathway also involves components of the ubiquitin-proteasome system, and regulates the abundance of cohesin proteins associated with meiotic chromosomes. As this pathway also appears to operate in embryonic stem cells, which are derived from early mouse embryos, we will use embryonic stem cell models to investigate how chromosome cohesion is regulated by the ubiquitin-proteasome system. We will use the mechanistic insights that we gain from embryonic stem cells to generate genetically modified mouse models to test whether manipulation of this pathway can slow the age-dependent loss of chromosome cohesion that occurs in post-natal mouse oocytes.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: REPRODUCTIVE HEALTH AND CHILDBIRTH