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The molecular biology of FMRP: new insights into fragile X syndrome

Abstract

Fragile X mental retardation protein (FMRP) is the product of the fragile X mental retardation 1 gene (FMR1), a gene that — when epigenetically inactivated by a triplet nucleotide repeat expansion — causes the neurodevelopmental disorder fragile X syndrome (FXS). FMRP is a widely expressed RNA-binding protein with activity that is essential for proper synaptic plasticity and architecture, aspects of neural function that are known to go awry in FXS. Although the neurophysiology of FXS has been described in remarkable detail, research focusing on the molecular biology of FMRP has only scratched the surface. For more than two decades, FMRP has been well established as a translational repressor; however, recent whole transcriptome and translatome analyses in mouse and human models of FXS have shown that FMRP is involved in the regulation of nearly all aspects of gene expression. The emerging mechanistic details of the mechanisms by which FMRP regulates gene expression may offer ways to design new therapies for FXS.

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Fig. 1: Brain cell types affected in fragile X syndrome.
Fig. 2: Functions of FMRP targets.
Fig. 3: Methods for the analysis of transcriptome-wide translation.
Fig. 4: Models of FMRP-mediated translational regulation.
Fig. 5: Regulation of nuclear functions by FMRP.
Fig. 6: Summary of FMRP’s activities.

References

  1. 1.

    Nelson, D. L., Orr, H. T. & Warren, S. T. The unstable repeats–three evolving faces of neurologic disease. Neuron 77, 825–843 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Wang, L. W., Berry-Kravis, E. & Hagerman, R. J. Fragile X: leading the way for targeted treatments in autism. Neurotherapeutics 7, 264–274 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Pieretti, M. et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66, 817–822 (1991).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Verkerk, A. J. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991).

    CAS  Article  Google Scholar 

  5. 5.

    Schaefer, G. B. & Mendelsohn, N. J. Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genet. Med. 10, 4–12 (2008).

    PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Li, Y. & Zhao, X. Concise review: Fragile X proteins in stem cell maintenance and differentiation. Stem Cell 32, 1724–1733 (2014).

    Article  CAS  Google Scholar 

  7. 7.

    Liu, B. et al. Regulatory discrimination of mRNAs by FMRP controls mouse adult neural stem cell differentiation. Proc Natl Acad Sci USA 115, E11397–E11405 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Berry-Kravis, E. M. et al. Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome. Nat. Rev. Drug Discov. 17, 280–299 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Zhao, X. & Bhattacharyya, A. Human models are needed for studying human neurodevelopmental disorders. Am. J. Hum. Genet. 103, 829–857 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Ashley, C. T. Jr., Wilkinson, K. D., Reines, D. & Warren, S. T. FMR1 protein: conserved RNP family domains and selective RNA binding. Science 262, 563–566 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Siomi, H., Siomi, M. C., Nussbaum, R. L. & Dreyfuss, G. The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. Cell 74, 291–298 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011). This article shows that FMRP ‘CLIPs’ to nearly 1,000 RNAs in the mouse brain, many of which encode proteins involved in synaptic function and are relevant to autism. In addition, it shows that most of the FMRP CLIP sites are in CDS of mRNA.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Udagawa, T. et al. Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat. Med. 19, 1473–1477 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Richter, J. D., Bassell, G. J. & Klann, E. Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat. Rev. Neurosci. 16, 595–605 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Hagerman, R. J. et al. Fragile X syndrome. Nat. Rev. Dis. Prim. 3, 17065 (2017).

    Article  Google Scholar 

  16. 16.

    Gross, C., Hoffmann, A., Bassell, G. J. & Berry-Kravis, E. M. Therapeutic strategies in fragile X syndrome: from bench to bedside and back. Neurotherapeutics 12, 584–608 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Bakker, C. E. & Oostra, B. A. Understanding fragile X syndrome: insights from animal models. Cytogenet. Genome Res. 100, 111–123 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Bhattacharyya, A. & Zhao, X. Human pluripotent stem cell models of fragile X syndrome. Mol. Cell Neurosci. 73, 43–51 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Garber, K. B., Visootsak, J. & Warren, S. T. Fragile X syndrome. Eur. J. Hum. Genet. 16, 666–672 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Sansone, S. M. et al. Improving IQ measurement in intellectual disabilities using true deviation from population norms. J. Neurodev. Disord. 6, 16 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Kaufmann, W. E. Autism spectrum disorder in fragile X syndrome: concurring conditions and current treatment. Pediatrics 139, S194–S206 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Shah, S. et al. FMRP control of ribosome translocation promotes chromatin modifications and alternative splicing of neuronal genes linked to autism. Cell Rep. 30, 4459–4472 (2020). The authors use dynamic ribosome profiling to identify mRNAs that are associated with FMRP-stalled ribosomes. A number of these RNAs encode chromatin-modifying enzymes, one of which alters histone H3 trimethylation at lysine 36 and alternative splicing of pre-mRNA.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Tan, M. H. et al. Dynamic landscape and regulation of RNA editing in mammals. Nature 550, 249–254 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Myrick, L. K., Hashimoto, H., Cheng, X. & Warren, S. T. Human FMRP contains an integral tandem Agenet (Tudor) and KH motif in the amino terminal domain. Hum. Mol. Genet. 24, 1733–1740 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Adinolfi, S. et al. The N-terminus of the fragile X mental retardation protein contains a novel domain involved in dimerization and RNA binding. Biochemistry 42, 10437–10444 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Ramos, A. et al. The structure of the N-terminal domain of the fragile X mental retardation protein: a platform for protein–protein interaction. Structure 14, 21–31 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Eberhart, D. E., Malter, H. E., Feng, Y. & Warren, S. T. The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. Hum. Mol. Genet. 5, 1083–1091 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Huang, J., Ikeuchi, Y., Malumbres, M. & Bonni, A. A Cdh1-APC/FMRP ubiquitin signaling link drives mGluR-dependent synaptic plasticity in the mammalian rain. Neuron 86, 726–739 (2016).

    Article  CAS  Google Scholar 

  30. 30.

    Muddashetty, R. S. et al. Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation and mGluR signaling. Mol. Cell 42, 673–688 (2012).

    Article  CAS  Google Scholar 

  31. 31.

    Kim, T. H. et al. Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates regulation of translation and deadenylation. Science 365, 825–829 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Tsang, B. et al. Phosphoregulated FMRP phase separation models activity-dependent translation through bidirectional control of mRNA granule formation. Proc. Natl Acad. Sci. USA 116, 4218–4227 (2019).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Althar, Y. M. & Joseph, S. RNA binding specificity of the human fragile X mental retardation protein. J. Mol. Biol. 432, 3851–3868 (2020).

    Article  CAS  Google Scholar 

  34. 34.

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

    CAS  Article  Google Scholar 

  35. 35.

    Vasilyev, N. et al. Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP. Proc. Natl Acad. Sci. USA 112, E5391–E5400 (2015).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Darnell, J. C. et al. Kissing complex RNAs mediate interaction between the fragile-X mental retardation protein KH2 domain and brain polyribosomes. Genes Dev. 19, 903–918 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Darnell, J. C., Fraser, C. E., Mostovetsky, O. & Darnell, R. B. Discrimination of common and unique RNA-binding activities among fragile X mental retardation protein paralogs. Hum. Mol. Genet. 18, 3164–3177 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    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).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

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

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Maurin, T. et al. HITS-CLIP in various brain areas reveals new targets and new modalities of RNA binding by fragile X mental retardation protein. Nucleic Acids Res. 46, 6344–6355 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Van Driesche, S. J. et al. FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types. Preprint at bioRxiv https://doi.org/10.1101/762500 (2019).

    Article  Google Scholar 

  42. 42.

    Sawicka, K. et al. FMRP has a cell-type-specific role in CA1 pyramidal neurons to regulate autism-related transcripts and circadian memory. eLife 8, e46919 (2019). The authors use FMRP conditional tag mice to perform cell type-specific FMRP target identification in mouse CA1 and cerebellar granule neurons and discover novel cell type-specific targets of FMRP.

    PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Zhang, J. et al. Fragile X-related proteins regulate mammalian circadian behavioral rhythms. Am. J. Hum. Genet. 83, 43–52 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Kwan, K. Y. et al. Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex. Cell 149, 899–911 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Doers, M. E. et al. iPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth. Stem Cell Dev. 23, 1777–1787 (2014).

    CAS  Article  Google Scholar 

  46. 46.

    Khalfallah, O. et al. Depletion of the fragile X mental retardation protein in embryonic stem cells alters the kinetics of neurogenesis. Stem Cell 35, 374–385 (2017).

    CAS  Article  Google Scholar 

  47. 47.

    Telias, M., Mayshar, Y., Amit, A. & Ben-Yosef, D. Molecular mechanisms regulating impaired neurogenesis of fragile X syndrome human embryonic stem cells. Stem Cell Dev. 24, 2353–2365 (2015).

    CAS  Article  Google Scholar 

  48. 48.

    Ascano, M. Jr. et al. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature 492, 382–386 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Tran, S. S. et al. Widespread RNA editing dysregulation in brains from autistic individuals. Nat. Neurosci. 22, 25–36 (2019). This article demonstrates that adenosine-to-inosine RNA editing is reduced in ASD and FXS brains and that FMRP modulates RNA editing through interaction with the RNA-editing enzyme ADAR. It also identifies FMRP target RNAs in adult human brains by CLIP–seq.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Li, M. et al. Identification of FMR1-regulated molecular networks in human neurodevelopment. Genome Res. 30, 361–374 (2020). The authors identify FMRP-binding targets using CLIP–seq in pure populations of human NPCs and neurons in either excitatory or inhibitory lineages differentiated from human pluripotent stem cells. They show both shared and unique FMRP targets in different cell types and human-specific FMRP targets.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Chasman, D., Fotuhi Siahpirani, A. & Roy, S. Network-based approaches for analysis of complex biological systems. Curr. Opin. Biotechnol. 39, 157–166 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Anderson, B. R., Chopra, P., Suhl, J. A., Warren, S. T. & Bassell, G. J. Identification of consensus binding sites clarifies FMRP binding determinants. Nucleic Acids Res. 44, 6649–6659 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Suhl, J. A., Chopra, P., Anderson, B. R., Bassell, G. J. & Warren, S. T. Analysis of FMRP mRNA target datasets reveals highly associated mRNAs mediated by G-quadruplex structures formed via clustered WGGA sequences. Hum. Mol. Genet. 23, 5479–5491 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    King, I. F. et al. Topoisomerases facilitate transcription of long genes linked to autism. Nature 501, 58–62 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Ahmad, M. et al. Topoisomerase 3beta is the major topoisomerase for mRNAs and linked to neurodevelopment and mental dysfunction. Nucleic Acids Res. 45, 2704–2713 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Lee, S. K. et al. Topoisomerase 3beta interacts with RNAi machinery to promote heterochromatin formation and transcriptional silencing in Drosophila. Nat. Commun. 9, 4946 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. 57.

    Xu, D. et al. Top3beta is an RNA topoisomerase that works with fragile X syndrome protein to promote synapse formation. Nat. Neurosci. 16, 1238–1247 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Feng, Y. et al. FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association. Mol. Cell 1, 109–118 (1997).

    CAS  Article  Google Scholar 

  59. 59.

    Khandjian, E. W., Corbin, F., Woerly, S. & Rousseau, F. The fragile X mental retardation protein is associated with ribosomes. Nat. Genet. 12, 91–93 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Dölen, G. et al. Correction of fragile X syndrome in mice. Neuron 56, 955–962 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Thomson, S. R. et al. Cell-type-specific translation profiling reveals novel strategy for treating fragile X syndrome. Neuron 95, 550–563 (2017). This work uses TRAP–seq to identify cell type-specific translational changes in hippocampal CA1 neurons as a result of FMRP deficiency. The authors identify muscarinic acetylcholine receptor 4 as a novel drug target to alleviate FMRP deficiency.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Ceolin, L. et al. Cell type-specific mRNA dysregulation in hippocampal CA1 pyramidal neurons of the fragile X syndrome mouse model. Front. Mol. Neurosci. 10, 340 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Ingolia, N. T., Ghaemmaghami, S., Newman, J. R. & Weissman, J. S. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218–223 (2012).

    Article  CAS  Google Scholar 

  64. 64.

    Liu, B. et al. Optimization of ribosome profiling using low-input brain tissue from fragile X syndrome model mice. Nucleic Acids Res. 47, e25 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Das Sharma, S. et al. Widespread alterations in translation elongation in the brain of juvenile Fmr1 knockout mice. Cell Rep. 26, 3313–3322 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. 66.

    Greenblatt, E. J. & Spradling, A. C. Fragile X mental retardation 1 gene enhances the translation of large autism-related proteins. Science 361, 709–712 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Shu, S. et al. FMRP links optimal codons to mRNA stability in neurons. Proc. Natl Acad. Sci. USA 117, 30400–30411 (2020). This work uses ribosome profiling and metabolic labelling of RNA to demonstrate that FMRP influences the relationship between codon optimality and RNA stability.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Hien, A., Molinaro, G., Liu, B., Huber, K. M. & Richter, J. D. Ribosome profiling in mouse hippocampus: plasticity-induced regulation and bidirecitonal controlby TSC2 and FMRP. Mol. Autism 14, 78 (2020).

    Article  CAS  Google Scholar 

  69. 69.

    Luo, Y. et al. Fragile X mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells. PLoS Genet. 6, e1000898 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. 70.

    Guo, W. et al. Inhibition of GSK3beta improves hippocampus-dependent learning and rescues neurogenesis in a mouse model of fragile X syndrome. Hum. Mol. Genet. 21, 681–691 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. 71.

    El-Brolosy, M. A. & Stainier, D. Y. R. Genetic compensation: a phenomenon in search of mechanisms. PLoS Genet. 13, e1006780 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72.

    Liu, T. et al. Direct measurement of the mechanical work during translocation by the ribosome. eLife 3, e03406 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73.

    Richter, J. D. & Coller, J. Pausing on polysomes: make way for elongation in translational control. Cell 16, 292–300 (2015).

    Article  CAS  Google Scholar 

  74. 74.

    Hanson, G. & Coller, J. Codon optimality, bias and usage in translation and mRNA decay. Nat. Rev. Mol. Cell. Biol. 19, 20–30 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Radhakrishnan, A. & Green, R. Connections underlying translation and mRNA stability. J. Mol. Biol. 428, 3558–3564 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Heck, A. M. & Wilusz, J. The interplay between the RNA decay and translation machinery in eukaryotes. Cold Spring Harb. Perspect. Biol. 10, a032839 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Zalfa, F. et al. A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability. Nat. Neurosci. 10, 578–587 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Zhang, F. et al. Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets. Hum. Mol. Genet. 27, 3936–3950 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Didiot, M. C., Subramanian, M., Flatter, E., Mandel, J. L. & Moine, H. Cells lacking the fragile X mental retardation protein (FMRP) have normal RISC activity but exhibit altered stress granule assembly. Mol. Biol. Cell 20, 428–437 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Valdez-Sinon, A. N. et al. Cdh1-APC regulates protein synthesis and stress granules in neurons through an FMRP-dependent mechanism. iScience 23, 101132 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Stoecklin, G. & Kedersha, N. Relationship of GW/P-bodies with stress granules. Adv. Exp. Med. Biol. 768, 197–211 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Perez-Ortin, J. E., Alepus, P., Chavez, S. & Choder, M. Eukaryotic mRNA decay: methodologies, pathways, and links to other stages of gene expression. J. Mol. Biol. 425, 3750–3775 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Jin, P. et al. Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nat. Neurosci. 7, 113–117 (2004).

    CAS  Article  Google Scholar 

  84. 84.

    Kenny, P. J. et al. MOV10 and FMRP regulate AGO2 association with microRNA recognition elements. Cell Rep. 9, 1729–1741 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Chen, E., Sharma, M. R., Shi, X., Agrawal, R. K. & Joseph, S. Fragile X mental retardation protein regulates translation by binding directly to the ribosome. Mol. Cell 54, 407–417 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Schenck, A., Bardoni, B., Moro, A., Bagni, C. & Mandel, J. L. A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P. Proc. Natl Acad. Sci. USA 98, 8844–8849 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    De Rubeis, S. et al. CYFIP1 Coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation. Neuron 79, 1169–1182 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. 88.

    Abekhoukh, S. et al. New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes. Dis. Model. Mech. 10, 463–474 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Meyer, K. D. & Jaffrey, S. R. Rethinking m6A readers, writers, and erasers. Ann. Rev. Cell Dev. Biol. 33, 319–342 (2017).

    CAS  Article  Google Scholar 

  90. 90.

    Zhao, B. S., Roundtree, I. A. & He, C. Post-transcriptional gene regulation by mRNA modifications. Nat. Rev. Mol. Cell Biol. 18, 31–42 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. 91.

    Edupuganti, R. R. et al. N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis. Nat. Struct. Mol. Biol. 24, 870–878 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Edens, B. M. et al. FMRP modulates neural differentiation through m6A-dependent mRNA nuclear export. Cell Rep. 28, 845–854 (2019). This article shows that FMRP preferentially binds m6A-methylated mRNAs and facilitates their nuclear export, which is important for NPC differentiation into neurons.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Engel, M. et al. The role of m6A/m-RNA methylation in stress response regulation. Neuron 99, 389–403 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Reich, D. P. & Bass, B. L. Mapping the dsRNA world. Cold Spring Harb. Perspect. Biol. 11, a035352 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Bhogal, B. et al. Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein. Nat. Neurosci. 14, 1517–1524 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Shamay-Ramot, A. et al. Fmrp interacts with Adar and regulates RNA editing, synaptic density and locomotor activity in zebrafish. PLoS Genet. 11, e1005702 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  97. 97.

    McMahon, A. C. et al. TRIBE: hijacking an RNA-editing enzyme to identify cell-specific targets of RNA-binding proteins. Cell 165, 742–753 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Korb, E. et al. Excess translation of epigenetic regulators contributes to fragile X syndrome and is alleviated by Brd4 inhibition. Cell 170, 1209–1223 (2017). This article demonstrates that FMRP controls the synthesis of epigenetic modifying enzymes that in turn alter the chromatin landscape, leading to transcriptional activation. The authors also use a small-molecule inhibitor of one these proteins and demonstrate rescue of several FXS-related phenotypes in mice.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Li, Y. et al. Reducing histone acetylation rescues cognitive deficits in a mouse model of Fragile X syndrome. Nat. Commun. 9, 2494 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  100. 100.

    Alpatov, R. et al. A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response. Cell 157, 869–881 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Guo, J. U. & Bartel, D. P. RNA G-quadruplexes are globally unfolded in eukaryotic cells and depleted in bacteria. Science 353, aaf5371 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 102.

    Pasciuto, E. & Bagni, C. SnapShot: FMRP interacting proteins. Cell 159, 218 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. 103.

    Lombard-Banek, C., Choi, S. B. & Nemes, P. Single-cell proteomics in complex tissue using microprobe capillary electrophoresis mass spectrometry. Methods Enzymol. 628, 263–292 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Schafer, S. T. et al. Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons. Nat. Neurosci. 22, 243–255 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Protic, D., Salcedo-Arellanom, M. J., Dym, J. B., Potter, L. A. & Hagerman, R. J. New targeted treatments for fragile X syndrome. Curr. Pediatr. Rev. 15, 251–258 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Gantois, I., Popic, J., Khoutorsky, A. & Sonenberg, N. Metformin for treatment of fragile X syndrome and other neurological disorders. Ann. Rev. Med. 70, 167–181 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. 107.

    Brown, V. et al. Purified recombinant Fmrp exhibits selective RNA binding as an intrinsic property of the fragile X mental retardation protein. J. Biol. Chem. 273, 15521–15527 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Devys, D., Lutz, Y., Rouyer, N., Bellocq, J. P. & Mandel, J. L. The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nat. Genet. 4, 335–340 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    Heiman, M. et al. A translational profiling approach for the molecular characterization of CNS cell types. Cell 135, 738–748 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Men, Y. et al. Astroglial FMRP deficiency cell-autonomously up-regulates miR-128 and disrupts developmental astroglial mGluR5 signaling. Proc. Natl Acad. Sci. USA 117, 25092–25103 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Jacobs, S., Cheng, C. & Doering, L. C. Hippocampal neuronal subtypes develop abnormal dendritic arbors in the presence of fragile X astrocytes. Neuroscience 324, 202–217 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  112. 112.

    Nyquist, P. A. & Hagerman, R. Genetics, white matter, and cognition: the effects of methylation on FMR1. Neurology 88, 2070–2071 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  113. 113.

    Wang, H. et al. Developmentally-programmed FMRP expression in oligodendrocytes: a potential role of FMRP in regulating translation in oligodendroglia progenitors. Hum. Mol. Genet. 13, 79–89 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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Acknowledgements

Work in the authors’ laboratories was supported by the NIH (U54HD082013, GM046779 and GM135087 to J.D.R., R01MH116582, MH118827 and R01NS105200 to X.Z and U54HD090256 to the Waisman Center), the Simons Foundation (to J.D.R.) and a Jenni and Kyle Professorship to X.Z.

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Correspondence to Joel D. Richter or Xinyu Zhao.

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Nature Reviews Neuroscience thanks B. Bardoni; R. Kelleher; E. Schuman; and N. Sonenberg, who co-reviewed with I. Gantois, for their contribution to the peer review of this work.

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Glossary

RNA-binding protein

Member of a family of proteins that frequently contain certain amino acid sequence motifs that have a strong avidity for single-stranded or double-stranded RNA.

Human pluripotent stem cells

Cells that have the capability to differentiate into any cell of the body.

Gene editing

Alteration (by insertion, deletion or substitution) of the nucleotide sequence within a gene, frequently by way of CRISPR–Cas9 technology.

mRNA splicing

The process by which precursor RNA is processed into mature RNA through removal of intron-derived sequences.

Next-generation sequencing

Massively parallel and ultra-high-throughput sequencing.

Gene network analysis

Analysis of gene involvement in two or more processes, which in turn may contain many genes that contribute to a given process.

mRNA codon bias

A situation where an mRNA does not contain all codons for a given amino acid in equal proportions.

N 6-Methyladenosine

(m6A). Adenosine methylated at the nitrogen at the 6 position.

Phase separation

Physical state of a protein that can form a membraneless separation between liquid and gel-like phases.

Secondary structures

In RNA, intramolecular base pairing.

Network-based integrative analysis

A process that seeks to integrate differential gene expression patterns based on calculated probability values with network-based meta-analysis to identify patterns of genes and pathways that may be impacted by underlying biological conditions such as disease.

Topoisomerase

An enzyme that unwinds DNA.

Ribosome translocation

The movement of a ribosome in the 5′ to 3′ direction as it translates mRNA sequence information into a polypeptide.

Stress granule

A membraneless subcellular organelle that forms in response to cellular stress and contains a variety of RNAs and proteins.

DNA damage response

The response of cells to identify and repair broken DNA strands.

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Richter, J.D., Zhao, X. The molecular biology of FMRP: new insights into fragile X syndrome. Nat Rev Neurosci (2021). https://doi.org/10.1038/s41583-021-00432-0

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