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Exosomes, Microcarriers and Regulated Secretion: Complex Forms of Inter-Cellular and Inter-Organism Communication

A male fruit fly gland showing secondary cells (small cluster at the tip of each 'arm' of the gland, green) and circumferential muscle fibres (shown as the dominant mass streaking across the gland, red/pink) © Clive Wilson
Male Drosophila accessory gland showing secondary cells (green) and circumferential muscle fibres (red)

We study the mechanisms by which cells package, secrete, store and dissipate signalling molecules and how these mechanisms affect physiological processes, such as growth and reproduction in health, and are disrupted in disease.

Our primary research questions

In multicellular organisms, cell-cell signalling plays a critical role in development and adult homeostasis, co-ordinating tissue and organ function. Traditionally, we consider secreted signals as single molecules, but it has become increasingly clear that they often function within multimolecular complexes. For example, they may be assembled in so-called dense-core granules inside secreting cells or associated with extracellular vesicles and lipid-containing structures. Exosomes are extracellular vesicles made in intracellular endosomal compartments, which are then secreted when these compartments fuse with the plasma membrane. Defects in exosome and other complex signalling are implicated in many physiological processes and in the pathology of several major human diseases, such as cancer, diabetes and neurodegenerative disorders. For example, in cancer, exosomes are thought to pass through the circulation and reprogramme normal target cells, so that they form a new niche for metastasis, while in flies, we have shown that exosomes in seminal fluid can reprogramme a female’s behaviour, so she rejects other males who approach her.

But how are complex signals of this kind assembled and their secretion regulated, and what physiological advantages do they offer? Our understanding in this major field of modern cell biology remains surprisingly limited. We have developed a new and unique genetic model in Drosophila, the fly accessory gland. One prostate-like cell type in this gland, the secondary cell, contains exosome- and dense-core-generating compartments that are thousands of times larger than in other cells in insects or mammals, allowing us to visualise some of the biogenesis processes involved for the first time in living tissue and in real time.

Combining this approach with inducible, cell type-specific genetic manipulations, we have been able to address several key questions in the field, showing (i) that exosomes are generated in recycling endosomes, in addition to late endosomes, a conserved process from fly to human, (ii) that formation of these exosomes is intimately linked to dense-core granule biogenesis and (iii) that the accessory gland can store proteins it secretes in lipid-containing structures called microcarriers that allow rapid dissipation of signals in their target organ, the female reproductive tract.

Our research objectives

Exosomes - Wilson Group 1. To understand the mechanisms by which exosomes and other extracellular vesicles are generated and secreted, and how they mediate their effects on target cells;
Dense-core granule formation and function - Wilson 2. To determine the processes that control regulated secretion of signalling molecules and particularly those signals that are packaged into dense-core granules;
Microcarriers - Wilson 3. To identify and analyse other extracellular multimolecular complexes, such as microcarriers, which store signals and permit their dissipation near target structures;
Prostate - Wilson 4. To characterise the signalling mechanisms that control prostate cancer growth and secretion, using our Drosophila accessory gland model;
5. To employ the Drosophila secondary cell to explore the mechanisms regulating other secretory and endosomal processes, and their links to diseases, such as endocrinological diseases, cancer, lysosomal storage disorders and neurodegenerative diseases. Examples of such mechanisms are given in the links to the other four objectives.

Why study the fly accessory gland?

The male accessory gland performs the equivalent functions to organs like the prostate gland and seminal vesicles in humans. We have shown that secondary cells in particular share properties with prostate cells, continuing to grow in adults, secreting exosomes that fuse to sperm in the female reproductive tract and growing under the control of a steroid receptor. We continue to investigate these parallels and are especially interested in the mechanisms by which growth controlled by this steroid receptor becomes hormone-independent following mating, mirroring changes seen in late-stage prostate cancer.

The tools available in Drosophila make it arguably the most genetically versatile animal model in the field of cell biology. But tissues, cells and subcellular structures in insects are typically small relative to mammals. In the fly accessory gland, secondary cells are a remarkable exception with giant lysosomes and secretory compartments, which contain enlarged dense-core granules and intraluminal vesicles that are secreted as exosomes, permitting real-time imaging of biogenesis processes that must typically be visualised by electron microscopy. Furthermore, the lumen of the gland is extremely large and fills with fluid in the first three days of adulthood, as the secretory epithelium develops and matures. It is this enlarged lumen that allowed us to identify microcarriers as a new form of signal storage.

For many years, our group has used Drosophila to provide new insights into the evolutionarily conserved biology that underpins normal cell functions, eg. Goberdhan et al., 1999; Goberdhan et al., 2005. Our most recent work has opened windows to the study of several previously intractable and uncharted areas of secretory biology, and suggests that further development of our understanding will have significant impact in several disease-related areas.

Interested in joining the group?

Whether you’re an aspiring undergraduate or graduate student, or an experienced researcher, who would like to use the accessory gland system to analyse a challenging cell biological question, we encourage you to contact us to find out more. You’ll also get the chance to interact with our collaborators, working in evolutionary and population biology, biotechnology, and biomedical and clinical science.

Our team

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