title: The conserved microRNA miR-8 tunes atrophin levels to prevent neurodegeneration in Drosophila.
abstract: 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.
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Janina S
authors.initials: JS
authors.lastname: Karres
authors.forename: Valérie
authors.initials: V
authors.lastname: Hilgers
authors.forename: Ines
authors.initials: I
authors.lastname: Carrera
authors.forename: Jessica
authors.initials: J
authors.lastname: Treisman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D001522:Behavior, Animal / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000502:physiology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009410:Nerve Degeneration / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D035683:MicroRNAs; D014157:Transcription Factors; C450826:gug protein, Drosophila; C526630:MIRN8 microRNA, Drosophila