The Drosophila adult male accessory gland (AG), which secretes many components of seminal fluid and modifies many behaviours of mated females, is a surprisingly understudied organ compared to many other fly tissues. This has been partly because of a lack of genetic tools allowing manipulation of the cell types that make up the AG epithelium. I have defined a set of transcriptional GAL4 drivers that display specific expression in a subset of AG epithelial cells known as secondary cells (SCs), and used these to investigate SC cell biology and whether there are biological parallels between SCs and the secretory cells of the human prostate. I show that these cells grow in an age-and mating-dependent manner relative to the rest of the epithelium. Furthermore, I have observed that these cells display the remarkable ability to delaminate apically from the epithelium after mating, migrate proximally within the gland in a directional manner, and can even be transferred intact to females during mating. A small-scale genetic screen was performed which established that BMP signalling plays a crucial role in these interesting features of SC biology. Specifically, BMP signalling activity is required for normal SC growth and migratory activity. Hyper-activation of the BMP signalling pathway drives SC overgrowth and promotes spontaneous delamination and migration at a high frequency. Intriguingly, I have also shown that ecdysone receptor (EcR) signalling, a steroid hormone signalling pathway, is an important positive regulator of SC growth. This is of particular interest given an analogous role that the androgen receptor (AR), also a steroid hormone receptor, plays as a potent driver of cell growth in the prostate epithelium. I also show that BMP signalling activity increases EcR expression levels in a cell type-specific fashion, via a potential protein stabilisation mechanism. A surprising discovery has been the observation that the cell cycle regulators, Rbf and E2F1, also genetically interact with EcR and promote SC growth. E2F1 activation drives normal SC growth and positively regulates EcR expression and activity. Many of these findings are reminiscent of biology observed in the human prostate and prostate cancer, where for example, AR expression and activity is driven by E2F1 activity. This mechanism is postulated to be of importance in the progression of prostate cancer to a disease that no longer responds to androgen deprivation therapy. In summary, my research in the Drosophila AG highlights several novel features of adult SC biology, including growth and migration, which are regulated by BMP and steroid hormone signalling activity. Much of this biology appears to closely parallel equivalent cell physiological phenomena in the prostate epithelium and in prostate cancer. In addition, as a consequence of this research, the Drosophila AG is emerging as an important model to study a number of conserved aspects of cell biology, particularly membrane trafficking, relevant to human diseases, including cancer.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:712496 |
| Date | January 2015 |
| Creators | Leiblich, Aaron |
| Contributors | Wilson, Clive ; Hamdy, Freddie |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://ora.ox.ac.uk/objects/uuid:77a5582b-df71-4198-a7af-0d16dec69230 |
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