microRNAs (miRNAs) bind to specific messenger RNA targets to posttranscriptionally modulate their expression. Understanding the regulatory relationships between miRNAs and targets remains a major challenge. Many miRNAs reduce expression of their targets to inconsequential levels. It has also been proposed that miRNAs might adjust target expression to an optimal level. Here we analyze the consequences of mutating the conserved miRNA miR-8 in Drosophila. We identify atrophin as a direct target of miR-8. miR-8 mutant phenotypes are attributable to elevated atrophin activity, resulting in elevated apoptosis in the brain and in behavioral defects. Reduction of atrophin levels in miR-8-expressing cells to below the level generated by miR-8 regulation is detrimental, providing evidence for a "tuning target" relationship between them. Drosophila atrophin is related to the atrophin family of mammalian transcriptional regulators, implicated in the neurodegenerative disorder DRPLA. The regulatory relationship between miR-8 and atrophin orthologs is conserved in mammals.
The Drosophila genes reaper, head involution defective (hid), and grim all reside at 75C on chromosome three and encode related proteins that have crucial functions in programmed cell death (reviewed in ). In this report, we describe a novel grim-reaper gene, termed sickle, that resides adjacent to reaper. The sickle gene, like reaper and grim, encodes a small protein which contains an RHG motif and a Trp-block. In wild-type embryos, sickle expression was detected in cells of the developing central nervous system. Unlike reaper, hid, and grim, the sickle gene is not removed by Df(3L)H99, and strong ectopic sickle expression was detected in the nervous system of this cell death mutant. sickle very effectively induced cell death in cultured Spodoptera Sf-9 cells, and this death was antagonized by the caspase inhibitors p35 or DIAP1. Strikingly, unlike the other grim-reaper genes, targeted sickle expression did not induce cell death in the Drosophila eye. However, sickle strongly enhanced the eye cell death induced by expression of either an r/grim chimera or reaper.
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