About the Project
Female fertility is dependent on successful ovulation. Within the ovary each oocyte is contained in a follicle where it is surrounded by a mass of cumulus cells. Prior to ovulation, a hormonal stimulus triggers the cumulus cells to secrete molecules that enable a jelly-like extracellular matrix to form around the oocyte. This is essential for ovulation; without the cumulus matrix the oocyte will either fail to be released from the ovary or, if it is released, it will not be fertilisable. The major component of the cumulus matrix is a carbohydrate known as hyaluronan. However, three proteins, TSG-6, PTX3 and inter-alpha-inhibitor (IaI), are essential for the organisation of the hyaluronan into a stable matrix; mice that don’t express any one of these proteins have defects in ovulation and are severely female sub-fertile (see [1-4]). We have identified a number of molecular mechanisms that likely contribute to the formation and organisation of the cumulus matrix [2-4] and we have a good understanding of the time frame over which this happens. However, there are still many details of this complex process that remain to be established.
This project will form part of on-going work to fully understand the molecular basis of ovulation, using both model systems and human samples. This might lead to improvements in the treatment of infertility. A broad range of state-of-the-art techniques will be used, including fluorescent microscopy, cell biology, protein interaction analyses, western blotting and mass spectrometry/proteomic analysis.
References
Milner, C.M., Higman, V.A. & Day, A.J. TSG-6: a pluripotent inflammatory mediator? (2006) Biochem. Soc. Trans. 34: 446-450.
Rugg, M.S., Willis, A.C., Mukhopadhyay, D., Hascall, V.C., Fries, E., Fülöp, C., Milner, C.M. & Day, A.J. Characterization of complexes formed between TSG-6 and inter-alpha-inhibitor as intermediates in the covalent transfer of heavy chains onto hyaluronan. (2005) J. Biol. Chem. 280: 25674-25686.
Ievoli, E., Lindstedt, R., Inforzato, A., Camaioni, A., Palone, F., Day, A.J., Mantovani, A., Salvatori, G. & Salustri, A. Implication of the oligomeric state of the N-terminal PTX3 domain in cumulus matrix assembly. (2011) Matrix Biol. 30: 330-337.
Baranova, N.S., Inforzato, A., Briggs, D.C., Tilakaratna, V., Enghild, J.J., Thakar, D., Milner, C.M., Day, A.J. & Richter, R.P. Incorporation of pentraxin 3 into hyaluronan matrices is tightly regulated and promotes matrix cross-linking. J. Biol. Chem., in press. Published as a “Paper in Press” on 4th September 2014.
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