Abstract
The importance of regulated necrosis in pathologies such as cerebral stroke and myocardial infarction is now fully recognized. However, the physiological relevance of regulated necrosis remains unclear. Here, we report a conserved role for p53 in regulating necrosis in Drosophila and mammalian spermatogenesis. We found that Drosophila p53 is required for the programmed necrosis that occurs spontaneously in mitotic germ cells during spermatogenesis. This form of necrosis involved an atypical function of the initiator caspase Dronc/Caspase 9, independent of its catalytic activity. Prevention of p53-dependent necrosis resulted in testicular hyperplasia, which was reversed by restoring necrosis in spermatogonia. In mouse testes, p53 was required for heat-induced germ cell necrosis, indicating that regulation of necrosis is a primordial function of p53 conserved from invertebrates to vertebrates. Drosophila and mouse spermatogenesis will thus be useful models to identify inducers of necrosis to treat cancers that are refractory to apoptosis.
MeSH terms
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Animals
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Apoptosis / genetics
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Caspase 9 / genetics
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Caspases / genetics
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Disease Models, Animal
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Drosophila Proteins / genetics
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Drosophila melanogaster / genetics
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Drosophila melanogaster / growth & development
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Germ Cells / growth & development
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Germ Cells / pathology
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Homeostasis / genetics
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Humans
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Hyperplasia / genetics
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Hyperplasia / pathology
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Male
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Mice
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Necrosis / genetics*
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Necrosis / pathology
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Spermatogenesis / genetics*
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Testis / growth & development
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Testis / metabolism
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Tumor Suppressor Protein p53 / genetics*
Substances
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Drosophila Proteins
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Tumor Suppressor Protein p53
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Caspase 9
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Caspases
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dronc protein, Drosophila
Grants and funding
This work was supported by a postdoctoral fellowship to FN from the Association Française contre les Myopathies, a European Union’s Seventh Framework Programme/AIRC (Associazione Italiana per la Ricerca sul cancro) Reintegration Grant to FN, and by Ligue Contre le Cancer (Comités de Savoie, Puy-de-Dôme and Rhône) and Foundation ARC grants to BM. EA is the incumbent of the Corinne S. Koshland Career Development Chair and is supported by grants from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC grant agreement (616088) and the Israel Science Foundation (921/13). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.