Linking reproductive behaviour and dense core granule biogenesis in secondary cells of the Drosophila male reproductive system

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All animals are formed from cells, each with their own functions, which work together to ensure that basic biological processes are kept in balance. To achieve this, neurons and many different cells within glands secrete signals in a controlled way. These signals instruct neighbouring or distant cells to change their behaviour when the normal balance is disturbed or when changes in the environment require the body to adjust accordingly. For example, beta cells in the pancreas secrete more insulin when blood sugar levels are raised, instructing other cells to take up the sugar and restore equilibrium, while nerve-like cells in the adrenal medulla release adrenaline in response to stress to prepare our bodies to fight or run.Cells involved in this regulated form of secretion share common features. They package the hormones or enzymes they release into special compartments, where the molecules are condensed into so-called dense core granules (DCGs) before secretion. Some mechanisms involved have been characterised in detail, but other aspects are poorly understood. For example, how do cells sense that they must rapidly replenish their DCGs after granule release? And how can this be co-ordinated with signals from the environment that alter secretion rates? While answering the first question relies on developing ways of testing how genes control the tiny compartments in which DCGs are formed, these compartments must also be studied in the whole animal to work out how they are affected by the environment. Since DCG control mechanisms go wrong in diseases like diabetes, where insulin secretion is defective, and cancer, where tumour cells signal inappropriately to normal cells around them, understanding how secretion is regulated has the potential to change the way we detect and treat these diseases.We are investigating this problem by studying special prostate-like cells called secondary cells (SCs) in the male reproductive system of the adult fruit fly. It is much easier to study the genetics behind secretion in flies than in animals like mice, and despite the fly's apparent simplicity, it shares remarkable similarities with humans. We have found that SCs have very large DCGs, some of which are released into seminal fluid each time a male fly mates. Mechanisms that control DCG formation in humans seem to be involved in making these compartments in SCs. But we have also found that molecules called BMPs, which are involved in sensing DCG release, instruct SCs to make new compartments, a mechanism that we think is conserved in mammals. In addition, we have been able to use a new type of super-resolution microscopy to watch the giant DCGs form in living glands for the first time, revealing other new features of this process.We now propose to work out the precise way in which BMPs control DCG formation and how brain activity during mating increases the BMP signal so more granules are made. In addition, we will test the importance of some of the new mechanisms for DCG control we have uncovered, such as the delivery of molecules to DCGs on nano-sized vesicles, which are also made by mammalian cells, but have not previously been linked to DCG formation.Overall, our proposed studies will use the unique biology of SCs and our ability to change their secretion using genetics and by mating flies to work out the ways in which different aspects of secretion are controlled in a living animal. Understanding the basic mechanisms involved may also help us to determine how they go wrong in other secreting cells: for example, in diseases like Type 2 diabetes, where faulty secretion leads to imbalance in the body's metabolic control systems, or cancer, where defective secretion can reprogramme normal cells to help tumour cells survive. We have already established collaborative links through our previous studies in flies to take this disease-led work forward as we gain new insights into the ways secretion is controlled from this project.