Reproductive Cell Biology
A central focus of our research concerns the mechanisms that regulate chromosome segregation during oogenesis. Oogenesis comprises a highly regulated series of differentiation steps in which diploid progenitors are programmed to become haploid and to regain the potential for pluripotency. This extraordinary transition occurs during meiosis and involves structural rearrangement of chromosomes; remodelling of telomeres, centromeres, and chromosome-associated proteins. Elucidating the mechanisms that regulate these processes is key to understanding the mechanisms that regulate embryonic stem cell behaviour, and to realising the therapeutic potential of somatic cell nuclear transfer.
We are using mouse and human oocytes to investigate cell cycle regulation during meiosis. Our results indicate that chromosome segregation in female meiosis requires critical functional modifications of a number of cell cycle regulators. We are currently addressing two important questions 1) How does the chromatin of a somatic cell (which has not been exposed to the remodelling events of meiotic prophase) interact with the meiotic regulatory milieu? 2) What is the mechanistic link between female reproductive senescence and aberrant chromosome segregation in oocytes? The latter is a collaborative project with Professor Tom Kirkwood, Institute of Ageing and Health.
In an extension of our interests in cell cycle regulation, we have recently embarked on a project to decipher the mechanisms regulating proliferation and genome surveillance during self-renewal of human embryonic stem (ES) cells. We are also working towards the production of clinical grade ES cells. This is a collaborative project with Professor Roger Pedersenâ€™s group, Cambridge and Professor Alison Murdoch, Newcastle Fertility Centre. We are also developing a GMP-compliant bio-processing system designed to optimise environmental conditions for ES cell derivation and nuclear transfer.
In collaboration with Professor Doug Turnbull, Institute of Neurosciences, we are investigating the mechanisms regulating replication and segregation of mitochondrial DNA in oocytes and early embryos. A translational application of this work is to optimise pronuclear transfer techniques in human zygotes with the ultimate aim of developing IVF-based strategies to prevent transmission of mitochondrial DNA mutations from mother to child.
Herbert M, Levasseur M, Homer H, Yallop K, Murdoch A, McDougall A (2003) Homologue disjunction in mouse oocytes requires proteolysis of securin and cyclin B1. Nat Cell Biol 5:1023-1025
Homer HA, McDougall A, Levasseur M, Yallop K, Murdoch AP, Herbert M (2005) Mad2 prevents aneuploidy and premature proteolysis of cyclin B and securin during meiosis I in mouse oocytes. Genes Dev 19:202-207
Brown DT, Herbert M, Lamb VK, Chinnery PF, Taylor RW, Lightowlers RN, et al. (2006) Transmission of mitochondrial DNA disorders: possibilities for the future. Lancet 368:87-89
Lyndsey Craven BSc
Muscular Dystrophy Campaign PhD Student
Linda Ferguson BSc
ONE NorthEast Technician
Louise Hyslop PhD
ONE NorthEast Research Associate
Lisa Lister BSc
MRC Junior Research Associate
Gareth Greggains BSc
Spitzer Foundation PhD Student
Sarah Pace BSc
Infertility Research Trust PhD Student
Rez Prathalingam PhD
ONE NorthEast Research Associate