Drosophila FMRP recruits the miRISC to target mRNAs to repress translation

Kaul, N.; Pradhan, S. J.; Boin, N. G.; Mason, M. M.; Rosales, J.; Starke, E. L.; Wilkinson, E. C.; Chapman, E. G.; Barbee, S. A.

doi:10.1101/2023.05.03.539280

bioRxiv · 10.1101/2023.05.03.539280

Drosophila FMRP recruits the miRISC to target mRNAs to repress translation

Kaul, N.·Pradhan, S. J.·Boin, N. G.·Mason, M. M.·Rosales, J.·Starke, E. L.·Wilkinson, E. C.·Chapman, E. G.·Barbee, S. A.

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Abstract

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is caused by mutations in the gene encoding for the Fragile X messenger ribonucleoprotein (FMRP). FMRP is an evolutionarily conserved and neuronally enriched RNA binding protein (RBP) with functions in the control of processes including RNA editing, RNA transport, and protein translation. Specific target RNAs play critical roles in neurodevelopment including the regulation of neurite morphogenesis, synaptic plasticity, and cognitive function. The different biological functions of FMRP are modulated by its cooperative interaction with distinct sets of neuronal RNA and protein binding partners. Here, we focus on interactions between FMRP and components of the microRNA (miRNA) pathway. Using the Drosophila model system, we show that dFMRP can repress the translation of a reporter mRNA via a deadenylation-independent mechanism. This repression requires the activity of both AGO1 and GW182, conserved components of the miRNA-containing RISC (miRISC). Interestingly, we find that dFMRP can bind directly to a short stem loop structure in the reporter and that dFMRP binding is a prerequisite for repression by miR-958. Finally, we show that dFmr1 interacts genetically with GW182 to control neurite morphogenesis. Collectively, these data suggest the dFMRP can directly recruit the miRISC to nearby miRNA binding sites and then repress translation via the activity of the miRISC effector, GW182.

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Kaul, N., Pradhan, S. J., Boin, N. G., Mason, M. M., Rosales, J., Starke, E. L., Wilkinson, E. C., Chapman, E. G., Barbee, S. A.. 2023-05-03. Drosophila FMRP recruits the miRISC to target mRNAs to repress translation. https://doi.org/10.1101/2023.05.03.539280

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