The efficient removal of dead cells is an important process in animal development and homeostasis. Cell corpses are often engulfed by professional phagocytes such as macrophages. However, some tissues have limited accessibility to circulating cells, and engulfment is carried out by neighboring non-professional phagocytes such as epithelial cells. The mechanisms of cell corpse recognition, engulfment and phagosome breakdown are only partially understood. The Drosophila ovary provides an excellent system for the study of engulfment by non-professional phagocytes. The ovary is closed to circulating cells, and degeneration of entire egg chambers can be induced easily by starvation. In such degenerating egg chambers, the germline nurse cells are engulfed by the surrounding somatic follicle cells. This engulfment process happens synchronously and rapidly at the onset of cell death, however the genetic requirements for follicle cell engulfment are completely unknown. This proposal aims to identify the genes and pathways required for engulfment by follicle cells. First, known engulfment genes and candidate signaling molecules will be investigated for their role in engulfment by follicle cells. Second, engulfing follicle cells will be isolated and their expression profiles will be compared to non-engulfing follicle cells using DNA microarray and proteomic approaches. Third, genetic screens will be conducted to identify new engulfment genes. Genes identified through these approaches will be characterized for their roles in engulfment in follicle cells and other tissues. These findings are expected to reveal the signaling mechanisms that are required for an epithelial cell to switch to an engulfing cell state. As the mechanisms of engulfment are highly conserved, these findings will have implications for the understanding and treatment of human diseases, including neurodegenerative and auto-immune disorders.
Billions of cells die every day in the human body, and these cells must be removed to prevent inappropriate immune responses. Defects in cell clearance can lead to inflammation and auto-immune disorders. This project will determine the genetic control of engulfment mechanisms in a tractable model organism.
| Santoso, Clarissa S; Meehan, Tracy L; Peterson, Jeanne S et al. (2018) The ABC Transporter Eato Promotes Cell Clearance in the Drosophila melanogaster Ovary. G3 (Bethesda) 8:833-843 |
| Meehan, Tracy L; Serizier, Sandy B; Kleinsorge, Sarah E et al. (2016) Analysis of Phagocytosis in the Drosophila Ovary. Methods Mol Biol 1457:79-95 |
| Etchegaray, Jon Iker; Elguero, Emma J; Tran, Jennifer A et al. (2016) Defective Phagocytic Corpse Processing Results in Neurodegeneration and Can Be Rescued by TORC1 Activation. J Neurosci 36:3170-83 |
| Meehan, Tracy L; Joudi, Tony F; Timmons, Allison K et al. (2016) Components of the Engulfment Machinery Have Distinct Roles in Corpse Processing. PLoS One 11:e0158217 |
| Timmons, Allison K; Mondragon, Albert A; Schenkel, Claire E et al. (2016) Phagocytosis genes nonautonomously promote developmental cell death in the Drosophila ovary. Proc Natl Acad Sci U S A 113:E1246-55 |
| Perkins, Lizabeth A; Holderbaum, Laura; Tao, Rong et al. (2015) The Transgenic RNAi Project at Harvard Medical School: Resources and Validation. Genetics 201:843-52 |
| Meehan, Tracy L; Kleinsorge, Sarah E; Timmons, Allison K et al. (2015) Polarization of the epithelial layer and apical localization of integrins are required for engulfment of apoptotic cells in the Drosophila ovary. Dis Model Mech 8:1603-14 |
| Meehan, Tracy L; Yalonetskaya, Alla; Joudi, Tony F et al. (2015) Detection of Cell Death and Phagocytosis in the Drosophila Ovary. Methods Mol Biol 1328:191-206 |
| Peterson, Jeanne S; Timmons, Allison K; Mondragon, Albert A et al. (2015) The End of the Beginning: Cell Death in the Germline. Curr Top Dev Biol 114:93-119 |
| Jenkins, Victoria K; Timmons, Allison K; McCall, Kimberly (2013) Diversity of cell death pathways: insight from the fly ovary. Trends Cell Biol 23:567-74 |
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