title: Engineered alterations in RNA editing modulate complex behavior in Drosophila: regulatory diversity of adenosine deaminase acting on RNA (ADAR) targets.
abstract: Select proteins involved in electrical and chemical neurotransmission are re-coded at the RNA level via the deamination of particular adenosines to inosine by adenosine deaminases acting on RNA (ADARs). It has been hypothesized that this process, termed RNA editing, acts to "fine-tune" neurophysiological properties in animals and potentially downstream behavioral outputs. However, the extreme phenotypes resulting from deletions of adar loci have precluded investigations into the relationship between ADAR levels, target transcripts, and complex behaviors. Here, we engineer Drosophila hypomorphic for ADAR expression using homologous recombination. A substantial reduction in ADAR activity (>80%) leads to altered circadian motor patterns and abnormal male courtship, although surprisingly, general locomotor coordination is spared. The altered phenotypic landscape in our adar hypomorph is paralleled by an unexpected dichotomous response of ADAR target transcripts, i.e. certain adenosines are minimally affected by dramatic ADAR reduction, whereas editing of others is severely curtailed. Furthermore, we use a novel reporter to map RNA editing activity across the nervous system, and we demonstrate that knockdown of editing in fruitless-expressing neurons is sufficient to modify the male courtship song. Our data demonstrate that network-wide temporal and spatial regulation of ADAR activity can tune the complex system of RNA-editing sites and modulate multiple ethologically relevant behavioral modalities.
authors.affiliation: From the Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912.
authors.forename: James E C
authors.initials: JEC
authors.lastname: Jepson
authors.affiliation: From the Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912.
authors.forename: Yiannis A
authors.initials: YA
authors.lastname: Savva
authors.affiliation: From the Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912.
authors.forename: Chio
authors.initials: C
authors.lastname: Yokose
authors.affiliation: From the Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912.
authors.forename: Arthur U
authors.initials: AU
authors.lastname: Sugden
authors.affiliation: From the Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912.
authors.forename: Asli
authors.initials: A
authors.lastname: Sahin
authors.affiliation: From the Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912. Electronic address: Robert_Reenan@brown.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Reenan
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D056426:Genetic Loci / Q000502:physiology*; D008124:Locomotion / Q000502:physiology; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D017393:RNA Editing / Q000502:physiology*; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C103226:fru protein, Drosophila; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase