Abstract
During Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs). Inhibiting apoptosis does not prevent PGC death, suggesting a divergence from the conventional apoptotic program. Here, we demonstrate that PGCs normally activate an intrinsic alternative cell death (ACD) pathway mediated by DNase II release from lysosomes, leading to nuclear translocation and subsequent DNA double-strand breaks (DSBs). DSBs activate the DNA damage-sensing enzyme, Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) and the ATR/Chk1 branch of the DNA damage response. PARP-1 and DNase II engage in a positive feedback amplification loop mediated by the release of PAR polymers from the nucleus and the nuclear accumulation of DNase II in an AIF- and CypA-dependent manner, ultimately resulting in PGC death. Given the anatomical and molecular similarities with an ACD pathway called parthanatos, these findings reveal a parthanatos-like cell death pathway active during Drosophila development.
Highlights
During Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs)
The PGCs are carried as a loose cluster into the posterior midgut pocket from where they migrate across the midgut epithelium near the embryo midline (ES 10; Fig. 1a)
In this study, we discovered a developmental form of the alternative cell death (ACD) pathway called parthanatos, by which PGCs undergo cell death during development, demonstrating that parthanatos is not limited to stress or pathological conditions
Summary
During Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs). We demonstrate that PGCs normally activate an intrinsic alternative cell death (ACD) pathway mediated by DNase II release from lysosomes, leading to nuclear translocation and subsequent DNA double-strand breaks (DSBs). Parthanatos has been implicated in the pathogenesis of several important diseases, including Parkinson’s disease, stroke, heart attack, diabetes, and ischemia reperfusion injury in numerous tissues[29,30,31] It remains unknown whether cell death by parthanatos is only limited to stress or pathological conditions, or if it might operate during normal development and homeostasis of the organism. Detailed analysis of the underlying mechanisms revealed striking resemblance to parthanatos; PGC death pathway is mediated by AIF-dependent nuclear translocation of the lysosomal nuclease, DNase II, and the consequent DNA damage induced PARP-1 activation. Given the rarity of developmental ACD pathways identified in metazoan model organisms, these findings may extend our understanding of the connections between the non-physiological and physiological ACD pathways, as well as when and why ACD may sometimes be advantageous over apoptosis
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