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

Nature Neuroscience volume 7, pages 113–117 (2004)Cite this article

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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References

  1. O'Donnell, W.T. & Warren, S.T. A decade of molecular studies of fragile X syndrome. Annu. Rev. Neurosci. 25, 315–338 (2002).

    Article  CAS  Google Scholar 

  2. Siomi, M.C. et al. FXR1, an autosomal homolog of the fragile X mental retardation gene. Embo J. 14, 2401–2408 (1995).

    Article  CAS  Google Scholar 

  3. Zhang, Y. et al. The fragile X mental retardation syndrome protein interacts with novel homologs FXR1 and FXR2. Embo J. 14, 5358–5366 (1995).

    Article  CAS  Google Scholar 

  4. Li, Z. et al. The fragile X mental retardation protein inhibits translation via interacting with mRNA. Nucleic Acids Res. 29, 2276–2283 (2001).

    Article  CAS  Google Scholar 

  5. Laggerbauer, B., Ostareck, D., Keidel, E.M., Ostareck-Lederer, A. & Fischer, U. Evidence that fragile X mental retardation protein is a negative regulator of translation. Hum. Mol. Genet. 10, 329–338 (2001).

    Article  CAS  Google Scholar 

  6. Comery, T.A. et al. Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc. Natl. Acad. Sci. USA 94, 5401–5404 (1997).

    Article  CAS  Google Scholar 

  7. Hinton, V.J., Brown, W.T., Wisniewski, K. & Rudelli, R.D. Analysis of neocortex in three males with the fragile X syndrome. Am. J. Med. Genet. 41, 289–294 (1991).

    Article  CAS  Google Scholar 

  8. Nimchinsky, E.A., Oberlander, A.M. & Svoboda, K. Abnormal development of dendritic spines in FMR1 knock-out mice. J. Neurosci. 21, 5139–5146 (2001).

    Article  CAS  Google Scholar 

  9. Feng, Y. et al. Fragile X mental retardation protein: nucleocytoplasmic shuttling and association with somatodendritic ribosomes. J. Neurosci. 17, 1539–1547 (1997).

    Article  CAS  Google Scholar 

  10. Bardoni, B. & Mandel, J.L. Advances in understanding of fragile X pathogenesis and FMRP function, and in identification of X linked mental retardation genes. Curr. Opin. Genet. Dev. 12, 284–293 (2002).

    Article  CAS  Google Scholar 

  11. Huber, K.M., Gallagher, S.M., Warren, S.T. & Bear, M.F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl. Acad. Sci. USA 99, 7746–7750 (2002).

    Article  CAS  Google Scholar 

  12. Schaeffer, C. et al. The fragile X mental retardation protein binds specifically to its mRNA via a purine quartet motif. Embo J. 20, 4803–4813 (2001).

    Article  CAS  Google Scholar 

  13. Brown, V. et al. Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell 107, 477–487 (2001).

    Article  CAS  Google Scholar 

  14. Darnell, J.C. et al. Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Cell 107, 489–499 (2001).

    Article  CAS  Google Scholar 

  15. Miyashiro, K.Y. et al. RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. Neuron 37, 417–431 (2003).

    Article  CAS  Google Scholar 

  16. Sung, Y.J. et al. The fragile X mental retardation protein FMRP binds elongation factor 1A mRNA and negatively regulates its translation in vivo. J. Biol. Chem. 278, 15669–15678 (2003).

    Article  CAS  Google Scholar 

  17. Zalfa, F. et al. The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell 112, 317–327 (2003).

    Article  CAS  Google Scholar 

  18. Ceman, S. et al. Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum. Mol. Genet. 12, 3295–3305 (2003).

    Article  CAS  Google Scholar 

  19. Cerutti, H. RNA interference: traveling in the cell and gaining functions? Trends Genet. 19, 39–46 (2003).

    Article  CAS  Google Scholar 

  20. Hammond, S.M., Caudy, A.A. & Hannon, G.J. Post-transcriptional gene silencing by double-stranded RNA. Nat. Rev. Genet. 2, 110–119 (2001).

    Article  CAS  Google Scholar 

  21. Pasquinelli, A.E. & Ruvkun, G. Control of developmental timing by microRNAs and their targets. Annu. Rev. Cell Dev. Biol. 18, 495–513 (2002).

    Article  CAS  Google Scholar 

  22. McManus, M.T. & Sharp, P.A. Gene silencing in mammals by small interfering RNAs. Nat. Rev. Genet. 3, 737–747 (2002).

    Article  CAS  Google Scholar 

  23. Bernstein, E., Caudy, A.A., Hammond, S.M. & Hannon, G.J. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 363–366 (2001).

    Article  CAS  Google Scholar 

  24. Carmell, M.A., Xuan, Z., Zhang, M.Q. & Hannon, G.J. The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. Genes Dev. 16, 2733–2742 (2002).

    Article  CAS  Google Scholar 

  25. Ishizuka, A., Siomi, M.C. & Siomi, H. A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. Genes Dev. 16, 2497–2508 (2002).

    Article  CAS  Google Scholar 

  26. Caudy, A.A., Myers, M., Hannon, G.J. & Hammond, S.M. Fragile X-related protein and VIG associate with the RNA interference machinery. Genes Dev. 16, 2491–2496 (2002).

    Article  CAS  Google Scholar 

  27. Jin, P. & Warren, S.T. New insights into fragile X syndrome: from molecules to neurobehaviors. Trends Biochem. Sci. 28, 152–158 (2003).

    Article  CAS  Google Scholar 

  28. Hammond, S.M., Boettcher, S., Caudy, A.A., Kobayashi, R. & Hannon, G.J. Argonaute2, a link between genetic and biochemical analyses of RNAi. Science 293, 1146–1150 (2001).

    Article  CAS  Google Scholar 

  29. Mourelatos, Z. et al. miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. Genes Dev. 16, 720–728 (2002).

    Article  CAS  Google Scholar 

  30. Bontekoe, C.J. et al. Knockout mouse model for Fxr2: a model for mental retardation. Hum. Mol. Genet. 11, 487–498 (2002).

    Article  CAS  Google Scholar 

  31. The Dutch-Belgian Fragile X Consortium. Fmr1 knockout mice: a model to study fragile X mental retardation. Cell 78, 23–33 (1994).

  32. Doi, N. et al. Short-interfering-RNA-mediated gene silencing in mammalian cells requires Dicer and eIF2C translation initiation factors. Curr. Biol. 13, 41–46 (2003).

    Article  CAS  Google Scholar 

  33. Wan, L., Dockendorff, T.C., Jongens, T.A. & Dreyfuss, G. Characterization of dFMR1, a Drosophila melanogaster homolog of the fragile X mental retardation protein. Mol. Cell. Biol. 20, 8536–8547 (2000).

    Article  CAS  Google Scholar 

  34. Zhang, Y.Q. et al. Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function. Cell 107, 591–603 (2001).

    Article  CAS  Google Scholar 

  35. Williams, R.W. & Rubin, G.M. ARGONAUTE1 is required for efficient RNA interference in Drosophila embryos. Proc. Natl. Acad. Sci. USA 99, 6889–6894 (2002).

    Article  CAS  Google Scholar 

  36. Kataoka, Y., Takeichi, M. & Uemura, T. Developmental roles and molecular characterization of a Drosophila homologue of Arabidopsis Argonaute1, the founder of a novel gene superfamily. Genes Cells 6, 313–325 (2001).

    Article  CAS  Google Scholar 

  37. Dockendorff, T.C. et al. Drosophila lacking dfmr1 activity show defects in circadian output and fail to maintain courtship interest. Neuron 34, 973–984 (2002).

    Article  CAS  Google Scholar 

  38. Martin, K.C. & Kosik, K.S. Synaptic tagging—who's it? Nat. Rev. Neurosci. 3, 813–820 (2002).

    Article  CAS  Google Scholar 

  39. Antar, L.N. & Bassell, G.J. Sunrise at the synapse: the FMRP mRNP shaping the synaptic interface. Neuron 37, 555–558 (2003).

    Article  CAS  Google Scholar 

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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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Author notes

  1. Stephanie Ceman & David L Nelson

    Present address: Department of Cell and Structural Biology, University of Illinois, 601 S. Goodwin Avenue, Urbana, Illinois, 61801, USA

Authors and Affiliations

  1. Department of Human Genetics, Emory University, 615 Michael Street, Atlanta, 30322, Georgia, USA

    Peng Jin, Stephanie Ceman, Mika Nakamoto, Julie Mowrey & Stephen T Warren

  2. Department of Cell Biology, Emory University, 615 Michael Street, Atlanta, 30322, Georgia, USA

    Daniela C Zarnescu & Kevin Moses

  3. Department of Genetics, University of Pennsylvania School of Medicine, 422 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Thomas A Jongens

  4. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    David L Nelson

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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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