Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein.
Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein.
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DOI：
10.1038/nn.2950
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发表时间：
2011-10-30
影响因子：
25
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中科院分区：
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FMR 1基因功能的丧失导致脆性X综合征（FXS），这是最常见的遗传性智力残疾形式。该基因座编码的蛋白质（FMRP）是一种RNA结合蛋白，被认为主要起翻译调节剂的作用，但最近的研究表明FMRP参与了其他基因调控机制。在这里，我们证明了果蝇脆性X同源物（dFMR 1）与A到I RNA编辑酶，dADAR的生化相互作用。我们发现，dAdar和dfmr1突变幼虫表现出不同的形态神经肌肉接头（NMJ）的缺陷。基于这些表型差异的上位性实验表明dAdar作用于dfmr1的下游，并且dFMR 1调节dADAR活性。此外，序列分析显示，dFMR 1的丢失或过表达影响某些dADAR靶标的编辑效率，这些dADAR靶标在突触传递中具有确定的作用。这些结果将dFMR 1与RNA编辑途径联系起来，并表明适当的NMJ突触结构需要dFMR 1调节dADAR活性。
Loss of FMR1 gene function results in fragile X syndrome (FXS), the most common heritable form of intellectual disability. The protein encoded from this locus (FMRP) is an RNA binding protein thought to primarily act as a translational regulator, however recent studies implicate FMRP in other mechanisms of gene regulation. Here, we demonstrate that the Drosophila fragile X homolog (dFMR1) biochemically interacts with the A-to-I RNA editing enzyme, dADAR. We found that dAdar and dfmr1 mutant larvae exhibit distinct morphological neuromuscular junction (NMJ) defects. Epistasis experiments based on these phenotypic differences suggest that dAdar acts downstream of dfmr1 and that dFMR1 modulates dADAR activity. Furthermore, sequence analyses revealed that 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.