Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein.
Loss of FMR1 gene function results in fragile X syndrome, the most common heritable form of intellectual disability. The protein encoded by this locus (FMRP) is an RNA-binding protein that is thought to primarily act as a translational regulator; however, recent studies have implicated FMRP in other mechanisms of gene regulation. We found that the Drosophila fragile X homolog (dFMR1) biochemically interacted with the adenosine-to-inosine RNA-editing enzyme dADAR. Adar and Fmr1 mutant larvae exhibited distinct morphological neuromuscular junction (NMJ) defects. Epistasis experiments based on these phenotypic differences revealed that Adar acts downstream of Fmr1 and that dFMR1 modulates dADAR activity. Furthermore, sequence analyses revealed that a loss or overexpression of dFMR1 affects editing efficiency on certain dADAR targets with defined roles in synaptic transmission. These results link dFMR1 with the RNA-editing pathway and suggest that proper NMJ synaptic architecture requires modulation of dADAR activity by dFMR1.
Department of Genetics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Balpreet
B
Bhogal
James E
JE
Jepson
Yiannis A
YA
Savva
Anita S-R
AS
Pepper
Robert A
RA
Reenan
Thomas A
TA
Jongens
D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D002461:Cell Line, Transformed; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D047468:Immunoprecipitation; D007814:Larva; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D009154:Mutation; D009469:Neuromuscular Junction / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D017393:RNA Editing / Q000235:genetics*; D016601:RNA-Binding Proteins; D009435:Synaptic Transmission; D014162:Transfection
D000243:Adenosine Deaminase; D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D016601:RNA-Binding Proteins; C467328:FMR1 protein, Drosophila; C567955:ADARB1 protein, human