RNA interference: a new mechanism by which FMRP acts in the normal brain? What can Drosophila teach us?
Fragile X syndrome is the most common heritable form of mental retardation caused by loss-of-function mutations in the FMR1 gene. The FMR1 gene encodes an RNA-binding protein that associates with translating ribosomes and acts as a negative translational regulator. Recent work in Drosophila melanogaster has shown that the fly homolog of FMR1 (dFMR1) plays an important role in regulating neuronal morphology, which may underlie the observed deficits in behaviors of dFMR1 mutant flies. Biochemical analysis has revealed that dFMR1 forms a complex that includes ribosomal proteins and, surprisingly, Argonaute2 (AGO2), an essential component of the RNA-induced silencing complex (RISC) that mediates RNA interference (RNAi) in Drosophila. dFMR1 also associates with Dicer, another essential processing enzyme of the RNAi pathway. Moreover, both a micro-RNA (miRNA) and short interfering RNAs (siRNAs) can coimmunoprecipitate with dFMR1. Together these findings suggest that dFMR1 functions in an RNAi-related apparatus to regulate the expression of its target genes at the level of translation. These findings raise the possibility that Fragile X syndrome may be the result of a protein synthesis abnormality caused by a defect in an RNAi-related apparatus. Because the core mechanisms of complex behaviors such as learning and memory and circadian rhythms appear to be conserved, studies of Fragile X syndrome using Drosophila as a model provide an economy-of-scale for identifying biological processes that likely underlie the abnormal morphology of dendritic spines and behavioral disturbances observed in Fragile X patients.
Siomi
Haruhiko
H
Institute for Genome Research, University of Tokushima, Kuramoto, Tokushima, Japan. siomi@genome.tokushima-u.ac.jp
Ishizuka
Akira
A
Siomi
Mikiko C
MC
D000818:Animals; D001921:Brain / Q000503:physiopathology; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000172:deficiency* / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008297:Male; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism
D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D016601:RNA-Binding Proteins; C467328:FMR1 protein, Drosophila