Research Opportunities

Undergraduate students, postgraduate students and postdoctoral fellows at all stages of their career interested in the study of reproduction are welcome to get in contact to consider options for research projects.  

Details on PhD programmes offered are available here: http://www.medsci.ox.ac.uk/study/graduate/wellcomedoctoralprogrammes/

The Society for Reproduction and Fertility (SRF) has numerous options for support and also run an Undergraduate Essay Competition (http://www.srf-reproduction.org/default.htm).

Current Research Programme 

My current research programme addresses 3 specific aspects of female reproductive function:

1. To investigate how the ovulation rate is regulated by the oocyte
2. To investigate the role of the oocyte in generating the basal lamina of the follicle
3. To investigate the physiology behind the onset of premature failure of the ovary

1. To investigate how the ovulation rate is regulated by the oocyte

Currently, it is unknown how fertility is regulated and why one species, such as humans, normally ovulate just one egg, whereas mice ovulate 8-10. I intend to investigate the regulation of female fertility using the T-syn mutant mouse, a novel mouse model of sustained increased fertility. 

T-syn mutants generate oocytes lacking the glycosyltransferase T-synthase. T-synthase (encoded by T-syn) is required to generate core 1-derived O-glycans. Female mice homozygous for the floxed T-syn allele and carrying a ZP3Cre transgene generate oocytes that lack T-syn from the primary stage onwards. ZP3 is expressed exclusively by oocytes from the primary stage onwards and thus all stages of development prior to this remain genetically unaltered. Therefore, all oocyte glycoproteins that normally carry core 1-derived O-glycans are modified. 

I intend to determine the molecular mechanisms that are modified resulting in oocytes lacking core 1-derived O-glycans promoting female mouse fertility. These investigations will further our understanding of the mechanisms that regulate fertility in different species and potentially we will be able to identify new targets for fertility treatments. 

2. To investigate the role of the oocyte in generating the basal lamina of the follicle

T-syn mutants also generate follicles that contain multiple oocytes - a phenomenon rarely seen in normal mice. Other mouse mutants with multiple-oocyte follicles (MOFs) have been described but the generation of these has been attributed to the abnormal breakdown of germ cell cysts just after birth. However, the genetic deletion in T-syn mutants occurs at a specific point of development in small, growing follicles which may occur up to a year after birth. Therefore, in T-syn mutants MOFs appear to form by the joining of adjacent follicles later in development. The basal lamina that surrounds the follicle is continually remodelled during follicle expansion and the basal lamina is known to regulate factors entering the follicle. Although, the cells and mechanisms involved in generating the basal lamina remain undefined, the generation of MOFs in T-syn mutant females clearly demonstrates a role for the oocyte. 

I aim to determine the role of the oocyte in the generation of the basal lamina and determine the molecular mechanisms involved in MOF formation. 

3. To investigate the physiology behind the onset of premature failure of the ovary

Premature ovarian failure (POF) affects 1% of women under 40 and in 70% the causes are unknown. There is clearly a need to understand more about the causes of POF, to generate treatments, to prevent its onset, and ideally to restore fertility. New models of premature ovarian failure are essential to further our understanding of the mechanisms involved in this condition. Double mutant mice have oocyte-specific deletion of two glycosyltransferase genes (T-syn and Mgat1) and their oocytes generate glycoproteins that lack both core 1-derived O-glycans and complex N-glycans. 

The deletion of T-syn and Mgat1 in double mutant oocytes leads to a complete demise of the functional mouse ovary by 3 months of age and is a new model for POF as characterized by ovarian follicle depletion, ovarian dysfunction, decreased sex steroids, and elevated gonadotrophins.

Most intriguingly, the genetic deletion in double mutant oocytes occurs early in follicle development and can occur at any time in adult life, yet mice are infertile only when older. Therefore why do follicles in the young mouse develop and ovulate whereas those in the older mouse cannot? I aim to determine how normal follicle development is terminated in double mutants. The project aims to determine how to restore fertility in double mutant females because double mutant ovaries still contain a normal complement of primordial germ cells. This would potentially identify targets to focus on for treatments for women with POF.

Suzannah Williams