Signaling mechanisms between dying cells and non-professional phagocytes in the Drosophila melanogaster ovary
Serizier, Sandy Bern
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Cell clearance is critical for the resolution of inflammation. Defects in cell clearance can result in pathologies associated with chronic inflammation. Cells are cleared by phagocytes. These phagocytes can be either professional phagocytes whose main function is to engulf, or non-professional phagocytes, which have other tissue-resident functions but can engulf when needed. While the molecular biology of cell clearance has been heavily studied, the differences between mechanisms of engulfment by non-professional and professional phagocytes are not yet known. The study of cell clearance by non-professional phagocytes is important due to the presence of these cells in all tissues of the human body. The Drosophila ovary is a genetically tractable, in vivo model system to study engulfment by non-professional phagocytes. In response to protein deprivation, apoptosis is induced in the germline and the surrounding follicle cells engulf the dying corpses. The back and forth signaling that occurs between the dying germline and engulfing epithelial follicle cells is critical for efficient death and clearance. The germline must display eat-me signals for phagocyte recognition. The interaction of the eat-me signal and the engulfment receptor allows follicle cells to activate downstream signaling for internalization and corpse degradation. Interestingly, engulfment receptors have an additional role in driving germline death progression. The research in this dissertation focuses on the signals that drive the reciprocal signaling between non-professional phagocytes and dying cells. The results of this study demonstrate that Draper, an engulfment receptor, induces germline cell death by activating a Shark/JNK/NADPH oxidase signaling axis that is dependent on a YxxL motif. The results from this work indicate that the apoptotic machinery is activated and nurse cell nuclei are degraded in response to Draper overexpression, but Draper-induced cell death occurs independent of effector caspases, indicating that Draper induces cell death via other death pathways. An unbiased, high throughput approach to identify novel death-inducing receptors and ligands is also described. This study describes the reciprocal signaling mechanisms between engulfing and dying cells and opens up new avenues for targeting engulfment-mediated cell death.