Abstract
Programmed cell death, or apoptosis, is a highly conserved cellular process that is crucial for tissue homeostasis under normal development as well as environmental stress. Misregulation of apoptosis is linked to many developmental defects and diseases such as tumour formation, autoimmune diseases and neurological disorders. In this paper, we show a novel role for the exoribonuclease Pacman/Xrn1 in regulating apoptosis. Using Drosophila wing imaginal discs as a model system, we demonstrate that a null mutation in pacman results in small imaginal discs as well as lethality during pupation. Mutant wing discs show an increase in the number of cells undergoing apoptosis, especially in the wing pouch area. Compensatory proliferation also occurs in these mutant discs, but this is insufficient to compensate for the concurrent increase in apoptosis. The phenotypic effects of the pacman null mutation are rescued by a deletion that removes one copy of each of the pro-apoptotic genes reaper, hid and grim, demonstrating that pacman acts through this pathway. The null pacman mutation also results in a significant increase in the expression of the pro-apoptotic mRNAs, hid and reaper, with this increase mostly occurring at the post-transcriptional level, suggesting that Pacman normally targets these mRNAs for degradation. Our results uncover a novel function for the conserved exoribonuclease Pacman and suggest that this exoribonuclease is important in the regulation of apoptosis in other organisms.
Highlights
Apoptosis, or programmed cell death, is crucial to normal embryonic development and metamorphosis of multicellular organisms, as well as being important in disease
We show that the 59-39 exoribonuclease Pacman/ Xrn1 regulates apoptosis in Drosophila wing imaginal discs
By staining the pcm14 discs for the Wingless protein, which is expressed in a distinct pattern in the mature wild-type L3 wing imaginal disc at 120 hours (Fig. 4E) (Couso et al, 1994) we showed that the wing discs at 120 hours had an incomplete pattern of Wingless expression (Fig. 4F) and were immature, whereas at 152 hours, when the majority of the mutant larvae are about to pupate, the pattern of Wingless expression was similar to wild type (Fig. 4G)
Summary
Programmed cell death, is crucial to normal embryonic development and metamorphosis of multicellular organisms, as well as being important in disease. The key components of apoptosis pathways are well known and highly conserved, and many of the signalling pathways that regulate apoptosis have been elucidated Posttranscriptional processes that work at the level of RNA stability are known to be important in a number of cellular processes [e.g. inflammation (Sanduja et al, 2011)] their contribution in the control of apoptosis are not well understood
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