Phagocytosis genes and the JNK signaling pathway promote developmental programmed cell death and are essential for engulfment of the dying germline in the Drosophila ovary
Timmons, Allison Karol
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Programmed cell death (PCD) and removal of cell corpses are important processes in animal development and homeostasis. Typically, engulfment of cell corpses is performed by professional phagocytes, such as macrophages. In tissues with limited accessibility to circulating cells, engulfment is carried out by neighboring non-professional phagocytes, such as epithelial cells. Compared to professional phagocytosis, the mechanisms that govern non-professional phagocytosis are not well characterized. The Drosophila ovary provides a powerful in vivo model for the study of PCD and engulfment by non-professional phagocytes. This dissertation identifies genetic pathways that govern non-professional phagocytosis during starvation-induced PCD and elucidates the major mechanism promoting non-apoptotic developmental PCD. During mid-oogenesis, germline nurse cells can be induced to die by starvation and their remnants are engulfed by surrounding epithelial follicle cells. We show that the engulfment receptor Draper is enriched and required in engulfing follicle cells. Additionally, we demonstrate that the JNK pathway is activated by Draper and required in engulfing follicle cells. Overexpression of Draper or the JNK pathway is sufficient to induce death of the germline, suggesting that there is coordination between the germline and follicular epithelium to promote cell death. Furthermore, activation of JNK bypasses the need for Draper in engulfment. These data demonstrate that JNK and Draper are crucial regulators of engulfment by non-professional phagocytes. During late oogenesis, nurse cells transfer their contents into the oocyte and undergo developmental PCD. Disruption of apoptosis or autophagy only partially inhibits PCD, indicating that other mechanisms contribute to the process. We demonstrate that the large-scale non-apoptotic developmental PCD in the Drosophila ovary occurs by a novel cell death program where follicle cells non-autonomously promote death of the germline. The phagocytic machinery of follicle cells, including Draper, JNK, and Ced-12, is essential for death and removal of nurse cells. Cell death events including acidification, nuclear envelope permeabilization, and DNA fragmentation are impaired when phagocytosis genes are inhibited. Moreover, elimination of a subset of follicle cells prevents nurse cell death and cytoplasmic dumping. Developmental PCD in the Drosophila ovary is an intriguing example of non-apoptotic, non-autonomous PCD, providing insight on the diversity of cell death mechanisms.