Snail family genes disrupt cell death and are required for stem cell maintenance in the Drosophila melanogaster ovary

Cell death is an integral part of oogenesis in the fruit fly, Drosophila melanogaster. When the fly is starved of protein, some pre-vitellogenic egg chambers die apoptotically. As egg chambers mature, excess germline cells die via a non-apoptotic, developmentally programmed death. Overexpression of the transcription factor escargot was found to block both death events in the ovary, which is very unusual. escargot overexpression blocked starvation-dependent death upstream of caspases, but still needed a death signal to produce undead egg chambers. In maturing egg chambers, escargot overexpression blocked death more effectively than disrupting both apoptosis and autophagy, indicating that it must affect non-apoptotic, non-autophagic death mechanisms. RNA-Seq and a genetic modifier screen were used to identify potential escargot targets that inhibit cell death. Studies were also undertaken to characterize the loss-of-function phenotype of escargot in the ovary. escargot is a member of the Snail family of transcription factors that play integral roles in development and gene regulation throughout Bilaterian organisms. In Drosophila melanogaster, the genes snail, escargot, and worniu are critical for stem cells in neuroblasts, gut, and testis, but a role in the ovary had not been shown. To analyze Snail family function in the ovary, I made a triple deficiency that removed the three Snail family members, called ΔSF. Surprisingly, ΔSF homozygous follicle stem cells are rapidly lost. Follicle stem cell loss was rescued by the expression of escargot or worniu but not snail, indicating that there is shared capability between genes. Moreover, follicle stem cells did not linger in the germarium, and their loss was not prevented by blocking apoptosis, indicating that the ΔSF defect is a failure of stem cell maintenance. Together, the results described in this dissertation show that Snail genes are needed for the normal function of the Drosophila ovary, and that escargot can regulate multiple kinds of cell death. Understanding Snail family genes is particularly important for the study of cancer, as they are implicated in mechanisms underlying the cancer stem cell state. Analysis of the highly conserved Snail family genes in Drosophila illuminates their function and dysfunction in human health and disease