Functional significance and regulation of the reproductive 'transferome'

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Even very simple creatures need to co-ordinate their activities. For example, the sea anemone has a simple net of connected neurons with which it can control the movements within its body wall. As organisms increase in complexity, there are ever more examples where coordinated control of bodily processes is required. We often know a lot about how individual components in these systems might function. However, we have a serious lack of knowledge about how groups of gene products are controlled in the highly precise and flexible way they often are. This is systems biology and is recognized as an increasingly important way in which to understand the complex world around us.Our focus is on a group of vitally important semen proteins transferred along with sperm - the 'transferome'. It has been realized for many decades seminal fluid proteins are far more than a simple sperm buffer. In fact they can cause profoundly important effects on female behaviour and physiology. These effects have been best studied in the fruitfly, which we use as the model system here. However, similar effects are also seen across a huge variety of animal taxa. It has been reported recently that the transfer of seminal fluid proteins by human males causes changes in the expression of immune genes in the female cervix. This is thought to prepare the womb for implantation as well as protecting against sexually transmitted infections.In the fruitfly there are about 130 semen proteins making up the transferome. They are made mostly in the male accessory glands (the fly equivalent of the human male prostate) the ejaculatory ducts and a few in the testes. They result in a huge variety of vitally important effects: they cause females to lay more eggs, to eat more (and of different types of foods), to be less sexually receptive to males, to switch on immune genes, to retain more sperm in storage, to show altered patterns of water balance and to sleep less! We also know from our own work that males can respond in a highly sophisticated and individually flexible manner to their social and sexual environment. When males are exposed to rivals they mate for longer when they meet a female and transfer more transferome components during those longer matings. This results in a higher number of offspring. Furthermore, there is recent evidence to show that the composition of the transferome can change in response to social context.Despite the importance of the transferome to both males and females and its high degree of flexibility, we know next to nothing about how it is controlled. However, we have gathered strong background data and have excellent experimental tools in the fruitfly to tackle this omission, giving us a unique and unparalleled opportunity to investigate for the first time the control of this complex and important system.We hypothesise that an effective way to regulate 130 individual components of the transferome is to manage them in 'sets' controlled by the same activator / inactivator. This facilitates the quick and co-ordinated release of groups of substances as soon as they are required, rather than trying to make them all individually from scratch. We predict that this level of control is achieved in practice by transcription factors that turn on the expression of genes and by different types of small RNAs that then bind to, repress and 'manage' gene sets. Our investigations provide strong evidence that is consistent with these predictions. What we propose here are important tests of these ideas by experimentally altering directly these different types of gene regulation and testing the effects on the control and function of the transferome. This will elucidate how it is that the transferome can be regulated with robustness, precision and flexibility.