Group leader: 

Ian Wilmut FRS, FRSE

Position: 

Professor of Reproductive Biology; Chairman SCRM

Contact: 

Ian [dot] Wilmut [at] ed [dot] ac [dot] uk

Aims
The aim of the group is to gain fundamental understanding of key regulatory mechanisms during early embryo development and to use that knowledge to establish new approaches to the study of inherited human diseases.

Background
New opportunities to study inherited human diseases were heralded by the development of the first methods for nuclear transfer in mammals.

One approach that was immediately apparent involves derivation of stem cells from embryos produced by transfer of a nucleus from a patient with an inherited disease. More recently the de-differentiation of murine somatic cells, achieved by Yamanaka and colleagues in Kyoto, by introduction of transcription factors suggests that the same goal may be achieved by direct treatment of somatic cells from a patient. Our aim is to understand the molecular events at fertilisation in order to formulate effective protocols for human nuclear transfer and reprogramming and to use those procedures in studying inherited diseases such as Motor Neuron Disease.

Approaches and progress
In studies of mechanisms of reprogramming after nuclear transfer we take advantage of the greater opportunity to study these events during fertilisation, because it is likely that reprogramming of gene expression during nuclear transfer depends upon the action of factors that initiate similar changes during fertilisation. Whereas nuclear transfer can only ever produce a modest number of embryos, by contrast oocytes and early embryos can be recovered in comparatively large numbers. We have described the changes in chromatin during fertilisation and demonstrated important differences after nuclear transfer. (In collaboration with Sari Pennings of the University of Edinburgh Centre for Cardiovascular Science).

In a search for active factors within the ovulated oocyte RNAi has been used to greatly reduce the level of candidates. In a proof of principle study we found that embryo development ceased at the early morula stage following reduction of the level of oocyte specific dnmt1 mRNA. A similar approach is now being followed in the mouse.

Reprogramming also occurs after fusion of somatic cells to embryo stem cells and is also amenable to analysis to identify active factors. We have evidence for remodelling of the nuclear lamina, chromatin remodelling and promoter-specific RNA transcription in human 293T cells by an extract derived from mouse ES cells over the course of a few hours’ exposure. This provides us with a method for identifying the factors that bring about the earliest changes in chromatin structure and gene expression during reprogramming by embryo stem cell extracts.

Methods of nuclear transfer are being developed in the rat in collaboration with John Mullins of the University of Edinburgh Centre for Cardiovascular Science). Although a small number of cloned rats have been produced in different laboratories the procedure is particularly inefficient and un-reproducible. This result may be associated with the fact that rat oocytes activate spontaneously much earlier after ovulation than oocytes of other species. Different approaches are being used to discover the under-pinning regulatory mechanisms and to control the time of activation.

Selected  publications

• Ribas RC, Taylor JE, McCorquodale C, Mauricio AC, Sousa M, Wilmut I. 2006. Effect of Zona Pellucida Removal on DNA Methylation in Early Mouse Embryos. Biol Reprod 74:307-313.
• Beaujean N, Hartshorne G, Cavilla J, Taylor J, Gardner J, Wilmut I, Meehan R, Young L. 2004. Non-conservation of mammalian preimplantation methylation dynamics.Curr Biol14(7):R266-267.
• Beaujean N, Taylor J, Gardner J, Wilmut I, Meehan R, Young L. 2004. Effect of Limited DNA Methylation Reprogramming in the Normal Sheep Embryo on Somatic Cell Nuclear Transfer.Biol Reprod 71(1):185-193.
• Theise ND, Wilmut I. 2003. Cell plasticity: flexible arrangement. Nature 425(6953):21.
• Gao S, Gasparrini B, McGarry M, Ferrier T, Fletcher J, Harkness L, De Sousa P, Wilmut I. 2002. Germinal vesicle material is essential for nucleus remodeling after nuclear transfer. Biol. Reprod. 67(3):928-934.

Funding
Biotechnology and Biological Sciences Research Council (BBSRC)
EU Sixth Framework Programme (EU FP6)