Identifying sperm-egg receptor pairs essential for mammalian fertilization to select new targets for fertility treatment and contraception.

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In humans and many other organisms, new life starts when a sperm and an egg recognise each other and permit the fusion of the membranes that surround them to form an embryo in a process we call fertilization. The way in which sperm and egg are able to recognise each other is very likely to involve a pair of recognition molecules: one displayed on the surface of the sperm and the other on the egg's surface that specifically bind to each other and finally enable the sperm and egg to fuse and create a genetically distinct embryo. Despite the fact that fertilization is a fundamental biological process our current molecular understanding is remarkably poor, particularly in mammals. This can be partly explained in humans due to the ethical issues involved, but there are also significant technical challenges that make working with sperm and eggs and the molecules on their surface in the laboratory very difficult. For example, eggs are a very rare cell type in mammals (humans usually release just a single egg each fertility cycle and mice less than ten) limiting the amount of biological material available. In addition, the interactions between cell surface recognition molecules are known to be extremely weak (often having half-lives of just fractions of a second), requiring the use of specialised approaches to detect them. The Cell Surface Signalling Laboratory at the Sanger Institute specialises in identifying these transient receptor interactions and we have developed a set of tools and techniques to circumvent these difficulties. We have recently shown, by identifying the first essential sperm-egg receptor pair (see Bianchi et al. Nature 2014 v508 p483), that applying these techniques can make important discoveries in this field. In this grant application, we propose to apply the same techniques in a systematic manner to identify additional sperm-egg recognition molecules but also begin to apply these findings to reveal new targets for fertility treatment and contraceptives. Identifying the cell surface receptors that are important for fertilization could have significant implications for the development of novel contraceptives and fertility treatments. For example, identifying which receptors are required for fertilization and how they interact could provide the starting point to develop new drugs that specifically block the interaction and therefore be used as a contraceptive. Perhaps surprisingly, no new contraceptives have been developed for over 40 years. The rapidly expanding human population (currently over 7 billion and predicted to reach 10 billion by 2050) has raised concerns globally that the limited resources on the planet will not sustain such a continued expansion. A drug that blocks the interaction between sperm and egg could conceivably be taken by both men and women and be effective for just a short period of time (a few hours to several days). It is also likely that the receptor interaction will be used by other animal species and so could be used to design methods to effectively control animal populations in a humane way.Finally, our previous work has shown that interactions between sperm and egg receptors can be essential for fertilization and so our planned research may reveal the identity of new infertility genes. Infertility is a growing problem, particularly in Western countries where the average age of couples having their first child has increased in recent years. By discovering new infertility genes, this research could open up the possibility of offering simple and inexpensive genetic screening tests to infertile couples that may guide their fertility treatment and save the expense and inconvenience of failed rounds of fertility treatment. In addition, by providing a molecular explanation for infertility, this may suggest methods of clinical intervention to help couples conceive.