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Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway

Abstract

Fragile X syndrome is caused by a loss of expression of the fragile X mental retardation protein (FMRP). FMRP is a selective RNA-binding protein which forms a messenger ribonucleoprotein (mRNP) complex that associates with polyribosomes. Recently, mRNA ligands associated with FMRP have been identified. However, the mechanism by which FMRP regulates the translation of its mRNA ligands remains unclear. MicroRNAs are small noncoding RNAs involved in translational control. Here we show that in vivo mammalian FMRP interacts with microRNAs and the components of the microRNA pathways including Dicer and the mammalian ortholog of Argonaute 1 (AGO1). Using two different Drosophila melanogaster models, we show that AGO1 is critical for FMRP function in neural development and synaptogenesis. Our results suggest that FMRP may regulate neuronal translation via microRNAs and links microRNAs with human disease.

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Figure 1: FMRP associates with endogenous microRNAs and Dicer activity.
Figure 2: The fragile X–related protein family associates with eIF2C2, a member of the Argonaute protein family.
Figure 3: Loss of AGO1 suppresses the rough eye phenotype caused by the overexpression of dFmr1.
Figure 4: AGO1 dominantly modulates dFmr1 function in synaptic growth and structure.

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Acknowledgements

The authors would like to thank G. Dreyfuss for anti-eIF2C2, anti-dFMR1 monoclonal 6A15 and anti-polyA binding protein antibodies, and J. Taylor and R. Apkarian for technical assistance. This work was supported, in part, by grants from the Rett Syndrome Research Foundation (P.J.), the FRAXA Research Foundation (D.Z.) and National Institute of Health grants to D.C.Z., S.C., T.A.G., D.L.N., K.M. and S.T.W.

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Correspondence to Stephen T Warren.

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Supplementary information

Supplementary Fig. 1

Proposed model of FMRP function via microRNA pathway. FMRP interacts with AGO1 and Dicer in vivo and may participate the processing of microRNA precursors into mature microRNAs. The G-quartet/stem structure is required for the initial recognition of its mRNA ligands by FMRP (low-specificity scanning). Once FMRP binds to its mRNA ligands, it will recruit AGO1 along with microRNAs to its mRNA ligands and facilitate the recognition of microRNA complementary sequence (high-specificity interrogation), which leads to efficient translation suppression. (PDF 54 kb)

Supplementary Methods (PDF 8 kb)

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Jin, P., Zarnescu, D., Ceman, S. et al. Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nat Neurosci 7, 113–117 (2004). https://doi.org/10.1038/nn1174

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