Functional dissection of Tmem95: a sperm cell surface protein essential for mammalian fertilization

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In humans, new life starts at fertilization when a sperm and an egg recognise each other and their surrounding membranes fuse to form a new embryo. Sperm and egg interact using cell surface recognition molecules which bind specifically and enable them to fuse together. Although fertilization is a fundamental biological process, our understanding of the molecules involved is remarkably poor, especially in mammals; for example, we do not know the molecule/s that are responsible for fusing the sperm and egg together. These knowledge gaps can be partly explained in humans due to the ethical issues surrounding fertilization, and the difficulties in studying cell surface molecules. For example, eggs are a very rare cell type, with humans usually releasing just a single egg in each fertility cycle limiting the amount of biological material available. In addition, the physical interactions between cell surface molecules are known to be very weak (having half-lives of just seconds), requiring the use of specialised methods to detect them. The Cell Surface Signalling Laboratory at the Sanger Institute specializes in identifying these fleeting interactions and we have developed a set of techniques to circumvent these difficulties. We have previously used these techniques to identify the first essential sperm-egg receptor pair (see Bianchi et al. Nature 2014 v508 p483), which made an important contribution to the molecular understanding of fertilization.We are excited about a new sperm surface protein prosaically named Tmem95 (for TransMEMbrane protein number 95) that is essential for the ability of sperm to fuse with eggs. Tmem95 was identified from research in the cattle industry where a case of idiopathic male infertility (sperm that is infertile despite looking and moving normally) was investigated. Researchers used the results of thousands of artificial inseminations performed in cows, and by careful record-keeping, identified the source to a mutation in the TMEM95 gene. Further research has shown that male mice which have an engineered mutation in their Tmem95 gene are also infertile because normal-looking sperm are unable to fuse with eggs in IVF assays. Humans also have a TMEM95 gene which looks very similar and we believe that it will have an important role in humans too; however, we know very little about this protein. This grant application is aimed at understanding more about the important role TMEM95 has in fertilization. Specifically, we will use our specialized technologies to determine the molecular identity the receptor it interacts with on the egg surface, describe how the protein is redistributed in the sperm during fertilization, establish if Tmem95 has a specific role in fusing membranes together, and investigate how it interacts with another essential sperm cell surface proteins called Izumo1.These studies will both further our molecular understanding of a fundamental biological process, and provide a foundation to develop better contraceptives and fertility treatments both in humans and in the farming industry. The rapidly expanding human population (currently over 7 billion and predicted to reach 10 billion by 2050) has raised concerns that the limited resources on the planet will not sustain a continued expansion. Paradoxically, 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 pain of failed rounds of IVF. These studies could also improve reproduction technologies in the livestock industry and also in the development of contraceptive vaccines to control wild animal populations and sterilize companion animals in an ethically more acceptable way other than culling or neutering.