Anatomy and Neuroscience - Theses
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ItemSnail - an important regulator of Drosophila GSC homeostasis( 2016)The Drosophila testis is a long coiled tube-like structure with male germline stem cells (GSCs) residing in the apical tip. 8-10 GSCs are arranged in a rosette shape around a group of somatic cells termed the hub, which secretes factors that regulate stem cell self-renewal. Due to asymmetrical division of GSCs, one daughter cell remains in direct contact with the hub and therefore maintains stem cell identity, while the other is displaced from the hub and commences differentiation to become a gonialblast. The gonialblast undergoes four rounds of mitotic divisions with incomplete cytokinesis, resulting in a cyst of sixteen interconnected spermatogonia which then progress through pre-meiotic S-phase and differentiate to become spermatocytes. There is a delicate balance between self-renewal of GSCs and differentiation of germ cells, which is required for tissue maintenance and regeneration. Snail proteins are zinc-finger DNA-binding proteins that act as transcriptional repressors of target genes via the binding to specific sequences termed ‘E-boxes’ in the promoter sequence. Drosophila has three Snail members which include: Snail, Escargot and Worniu, while the mammalian Snail family is comprised of Snai1/Snail, Snai2/Slug and Snai3/smuc. Snail proteins play a crucial role in initiating epithelial to mesenchymal transitions (EMT), both in normal physiology and disease. This project reveals an important role for the transcription factor Snail in the regulation of GSC maintenance. I have utilised a dominant negative transgene of escargot (esgDN) in order to block the function of all three Snail family members, which resulted in a severe GSC loss phenotype. Only the expression of a WT snail transgene was able to partially rescue the phenotype. Despite its high expression in somatic cells and spermatogonia, loss of Escargot function in GSCs has no effect. Conversely, I showed that snail is expressed in very low levels in the germline but snail mutant GSCs are lost from the niche. My results demonstrate that the loss of GSCs is not due to cell death or misregulated differentiation, but due to a disruption in adhesion of GSCs to the hub, which ultimately results in loss of GSC identity. Snail proteins were previously shown to have an important role in mammalian gonads, thus suggesting a conserved role for Snail in regulating spermatogenesis.