title: Defective escape behavior in DEAH-box RNA helicase mutants improved by restoring glycine receptor expression.
abstract: RNA helicases regulate RNA metabolism, but their substrate specificity and in vivo function remain largely unknown. We isolated spontaneous mutant zebrafish that exhibit an abnormal dorsal bend at the beginning of tactile-evoked escape swimming. Similar behavioral defects were observed in zebrafish embryos treated with strychnine, which blocks glycine receptors (GlyRs), suggesting that the abnormal motor response in mutants may be attributable to a deficit in glycinergic synaptic transmission. We identified a missense mutation in the gene encoding RNA helicase Dhx37. In Dhx37 mutants, ribosomal RNA levels were unchanged, whereas GlyR α1, α3, and α4a subunit mRNA levels were decreased due to a splicing defect. We found that Dhx37 can interact with GlyR α1, α3, and α4a transcripts but not with the GlyR α2 subunit mRNA. Overexpression of GlyR α1, α3, or α4a subunits in Dhx37-deficient embryos restored normal behavior. Conversely, antisense-mediated knockdown of multiple GlyR α subunits in wild-type embryos was required to recapitulate the Dhx37 mutant phenotype. These results indicate that Dhx37 is specifically required for the biogenesis of a subset of GlyR α subunit mRNAs, thereby regulating glycinergic synaptic transmission and associated motor behaviors. To our knowledge, this is the first identification of pathologically relevant substrates for an RNA helicase.
authors.affiliation: Center for Frontier Research, National Institute of Genetics, Mishima 411-8540, Japan, Department of Genetics, Graduate University for Advanced Studies (SOKENDAI), Mishima 411-8540, Japan, PRESTO, Japan Science and Technology Agency, Osaka 567-0047, Japan, and Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, United Kingdom.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hirata
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Ogino
authors.forename: Kenta
authors.initials: K
authors.lastname: Yamada
authors.forename: Sophie
authors.initials: S
authors.lastname: Leacock
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harvey
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000166:cytology; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004625:Embryo, Nonmammalian; D004924:Escape Reaction / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D018684:Glycine Agents / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010812:Physical Stimulation / Q000009:adverse effects; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism*; D013331:Strychnine / Q000494:pharmacology; D013550:Swimming / Q000502:physiology; D013569:Synapses / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D014741:Video Recording; D015027:Zebrafish
chemical_list: D018684:Glycine Agents; D020319:Oligodeoxyribonucleotides, Antisense; D021122:Protein Subunits; D012333:RNA, Messenger; D018009:Receptors, Glycine; D053487:DEAD-box RNA Helicases; D013331:Strychnine
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