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Programmed Necrosis

Ludivine Walter

The field of cell death was recently revitalized by the understanding that necrosis is a highly regulated and genetically controlled process. Necrosis is defined as a regulated cell death process that eventually results in cell leakage and is morphologically characterized by cytoplasmic granulation and cellular/organelles swelling (oncosis). Several forms of regulated necrosis share these morphological features but can be induced by distinct pathways. The mostly studied form of necrosis, necroptosis, is induced by the TNF superfamily of receptors (TNFR) and a signaling cascade involving the kinases RIPK1 and/or RIPK3. Other forms of necrosis are independent of TNFR and RIP kinases and often involve oxidative stress, with a predominant role of mitochondria.

Recent work has shown that during adult Drosophila spermatogenesis, 20% of spermatogonial cysts are eliminated by spontaneous germ cell death through necrosis. We found that necrotic cell death is required to maintain cellular homeostasis during spermatogenesis. Importantly, prevention of necrosis resulted in hyperplasia, a tumor-like phenotype, in the testes, which was reversed by restoring necrosis specifically in spermatogonia. The Drosophila genome does not encode a RIPK homolog, providing us with a unique genetic model to investigate the mechanisms of physiological necrosis independently of RIP kinases.