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Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice

Abstract

Fragile X syndrome results from a loss of the RNA-binding protein fragile X mental retardation protein (FMRP). How FMRP regulates neuronal development and function remains unclear. Here we show that FMRP-deficient immature neurons exhibit impaired dendritic maturation, altered expression of mitochondrial genes, fragmented mitochondria, impaired mitochondrial function, and increased oxidative stress. Enhancing mitochondrial fusion partially rescued dendritic abnormalities in FMRP-deficient immature neurons. We show that FMRP deficiency leads to reduced Htt mRNA and protein levels and that HTT mediates FMRP regulation of mitochondrial fusion and dendritic maturation. Mice with hippocampal Htt knockdown and Fmr1-knockout mice showed similar behavioral deficits that could be rescued by treatment with a mitochondrial fusion compound. Our data unveil mitochondrial dysfunction as a contributor to the impaired dendritic maturation of FMRP-deficient neurons and suggest a role for interactions between FMRP and HTT in the pathogenesis of fragile X syndrome.

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Fig. 1: Specific deletion of FMRP from immature neurons leads to reduced neuronal number.
Fig. 2: FMRP-deficient DCX+ immature neurons in the adult DG exhibited impaired maturation.
Fig. 3: Metabolic process–related genes changed in FMR1-deficient developing neurons.
Fig. 4: Impaired mitochondrial fusion in FMRP-deficient DCX+ immature neurons.
Fig. 5: Restoration of mitochondrial fusion rescues FMRP-deficient immature neurons.
Fig. 6: FMRP-deficient immature neurons exhibited reduced HTT expression, and downregulation of HTT led to impaired dendritic maturation.
Fig. 7: Increasing the expression levels of HTT rescued mitochondrial fusion deficits of FMRP-deficient neurons.
Fig. 8: Increasing the expression levels of HTT rescued dendritic complexity deficits of FMRP-deficient neurons.

Code availability

Transcriptome data for this project are available on the Gene Expression Omnibus (accession number GSE117111). We have used only published software and freely accessible software for data analyses. Further details can be requested from the corresponding author.

Data availability

Source data associated with Fig. 3 can be accessed through GEO: GSE117111. All data are reported in the main text and supplementary materials, stored at the University of Wisconsin-Madison and are available from the corresponding author upon request.

References

  1. 1.

    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  Google Scholar 

  2. 2.

    Hagerman, R. J. & Polussa, J. Treatment of the psychiatric problems associated with fragile X syndrome. Curr. Opin. Psychiatry 28, 107–112 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Irwin, S. A. et al. Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am. J. Med. Genet. 98, 161–167 (2001).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Telias, M., Kuznitsov-Yanovsky, L., Segal, M. & Ben-Yosef, D. Functional deficiencies in fragile X neurons derived from human embryonic stem cells. J. Neurosci. 35, 15295–15306 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Telias, M., Segal, M. & Ben-Yosef, D. Immature responses to GABA in fragile X neurons derived from human embryonic stem cells. Front. Cell Neurosci. 10, 121 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Contractor, A., Klyachko, V. A. & Portera-Cailliau, C. Altered neuronal and circuit excitability in fragile X syndrome. Neuron 87, 699–715 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Guo, W. et al. Fragile X proteins FMRP and FXR2P control synaptic GluA1 expression and neuronal maturation via distinct mechanisms. Cell Rep. 11, 1651–1666 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    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 

  12. 12.

    Devine, M. J. & Kittler, J. T. Mitochondria at the neuronal presynapse in health and disease. Nat. Rev. Neurosci. 19, 63–80 (2018).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Wakabayashi, J. et al. The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J. Cell. Biol. 186, 805–816 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Ishihara, N. et al. Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat. Cell Biol. 11, 958–966 (2009).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Li, Z., Okamoto, K., Hayashi, Y. & Sheng, M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119, 873–887 (2004).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Steib, K., Schäffner, I., Jagasia, R., Ebert, B. & Lie, D. C. Mitochondria modify exercise-induced development of stem cell-derived neurons in the adult brain. J. Neurosci. 34, 6624–6633 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Schon, E. A. & Przedborski, S. Mitochondria: the next (neurode)generation. Neuron 70, 1033–1053 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Qin, M., Kang, J. & Smith, C. B. Increased rates of cerebral glucose metabolism in a mouse model of fragile X mental retardation. Proc. Natl Acad. Sci. USA 99, 15758–15763 (2002).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Davidovic, L. et al. A metabolomic and systems biology perspective on the brain of the fragile X syndrome mouse model. Genome Res. 21, 2190–2202 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Lima-Cabello, E. et al. An abnormal nitric oxide metabolism contributes to brain oxidative stress in the mouse model for the fragile X syndrome, a possible role in intellectual disability. Oxid. Med. Cell Longev. 2016, 8548910 (2016).

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    el Bekay, R. et al. Enhanced markers of oxidative stress, altered antioxidants and NADPH-oxidase activation in brains from Fragile X mental retardation 1-deficient mice, a pathological model for Fragile X syndrome. Eur. J. Neurosci. 26, 3169–3180 (2007).

    PubMed  Article  Google Scholar 

  22. 22.

    Lumaban, J. G. & Nelson, D. L. The Fragile X proteins Fmrp and Fxr2p cooperate to regulate glucose metabolism in mice. Hum. Mol. Genet. 24, 2175–2184 (2015).

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Bechara, E. G. et al. A novel function for fragile X mental retardation protein in translational activation. PLoS Biol. 7, e16 (2009).

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Guo, W. et al. Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning. Nat. Med. 17, 559–565 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Guo, W. et al. Inhibition of GSK3β 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  Google Scholar 

  26. 26.

    Li, Y. et al. MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome. Sci. Transl. Med. 8, 336ra61 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27.

    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 

  28. 28.

    Kempermann, G., Song, H. & Gage, F. H. Neurogenesis in the AdultHippocampus. Cold Spring Harb. Perspect. Biol. 7, a018812 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29.

    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 

  30. 30.

    Gao, Y. et al. Integrative single-cell transcriptomics reveals molecular networks defining neuronal maturation during postnatal neurogenesis. Cereb. Cortex 27, 2064–2077 (2017).

    PubMed  Article  Google Scholar 

  31. 31.

    Li, M. et al. Establishment of reporter lines for detecting fragile X mental retardation (FMR1) gene reactivation in human neural cells. Stem Cells 35, 158–169 (2017).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Wang, D. et al. A small molecule promotes mitochondrial fusion in mammalian cells. Angew. Chem. Int. Ed. Engl. 51, 9302–9305 (2012).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Carmo, C., Naia, L., Lopes, C. & Rego, A. C. Mitochondrial Dysfunction in Huntington’s Disease. Adv. Exp. Med. Biol. 1049, 59–83 (2018).

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Konermann, S. et al. Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature 517, 583–588 (2015).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Sidhu, H., Dansie, L. E., Hickmott, P. W., Ethell, D. W. & Ethell, I. M. Genetic removal of matrix metalloproteinase 9 rescues the symptoms of fragile X syndrome in a mouse model. J. Neurosci. 34, 9867–9879 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. 36.

    Dolan, B. M. et al. Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486. Proc. Natl Acad. Sci. USA 110, 5671–5676 (2013).

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Niu, B. et al. GRK5 regulates social behavior via suppression of mTORC1 signaling in medial prefrontal cortex. Cereb. Cortex 28, 421–432 (2018).

    PubMed  Article  Google Scholar 

  38. 38.

    Pratt, K. G., Zimmerman, E. C., Cook, D. G. & Sullivan, J. M. Presenilin 1 regulates homeostatic synaptic scaling through Akt signaling. Nat. Neurosci. 14, 1112–1114 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Kaplan, E. S. et al. Early mitochondrial abnormalities in hippocampal neurons cultured from Fmr1 pre-mutation mouse model. J. Neurochem. 123, 613–621 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Ross-Inta, C. et al. Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome. Biochem. J. 429, 545–552 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Westermann, B. Mitochondrial fusion and fission in cell life and death. Nat. Rev. Mol. Cell Biol. 11, 872–884 (2010).

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Chen, H. et al. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J. Cell. Biol. 160, 189–200 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Filadi, R., Pendin, D. & Pizzo, P. Mitofusin 2: from functions to disease. Cell Death Dis. 9, 330 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Pham, A. H., Meng, S., Chu, Q. N. & Chan, D. C. Loss of Mfn2 results in progressive, retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit. Hum. Mol. Genet. 21, 4817–4826 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Berthet, A., Margolis, E. B., Zhang, J., Hsieh, I. & Zhang, J. Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons. J. Neurosci. 34, 14304–14317 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Jiang, S. et al. Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex. Mol. Neurodegener. 13, 5 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. 47.

    Fang, D., Yan, S., Yu, Q., Chen, D. & Yan, S. S. Mfn2 is required for mitochondrial development and synapse formation in human induced pluripotent stem cells/hiPSC derived cortical neurons. Sci. Rep. 6, 31462 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Shirendeb, U. et al. Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington’s disease: implications for selective neuronal damage. Hum. Mol. Genet. 20, 1438–1455 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Ochaba, J. et al. Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc. Natl Acad. Sci. USA 111, 16889–16894 (2014).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Culver, B. P. et al. Huntington’s disease protein huntingtin associates with its own mRNA. J. Huntingtons Dis 5, 39–51 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Mientjes, E. J. et al. The generation of a conditional Fmr1 knock out mouse model to study Fmrp function in vivo. Neurobiol. Dis. 21, 549–555 (2006).

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Wang, X., Qiu, R., Tsark, W. & Lu, Q. Rapid promoter analysis in developing mouse brain and genetic labeling of young neurons by doublecortin-DsRed-express. J. Neurosci. Res. 85, 3567–3573 (2007).

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Lagace, D. C. et al. Dynamic contribution of nestin-expressing stem cells to adult neurogenesis. J. Neurosci. 27, 12623–12629 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Smrt, R. D. et al. Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons. Neurobiol. Dis. 27, 77–89 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Zhao, C., Teng, E. M., Summers, R. G. Jr., Ming, G. L. & Gage, F. H. Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J. Neurosci. 26, 3–11 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    Vivar, C. et al. Monosynaptic inputs to new neurons in the dentate gyrus. Nat. Commun. 3, 1107 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. 58.

    Bu, Q., Wang, A. & Hamzah, H. CREB signaling is involved in rett syndrome pathogenesis. J. Neurosci. 37, 3671–3685 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Smrt, R. D. et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 28, 1060–1070 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Doench, J. G. et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat. Biotechnol. 34, 184–191 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Hsu, P. D. et al. DNA targeting specificity of RNA-guided Cas9 nucleases. Nat. Biotechnol. 31, 827–832 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Barkho, B. Z. et al. Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote the differentiation and migration of adult neural progenitor cells in response to chemokines. Stem Cells 26, 3139–3149 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Li, X. et al. Epigenetic regulation of the stem cell mitogen Fgf-2 by Mbd1 in adult neural stem/progenitor cells. J. Biol. Chem. 283, 27644–27652 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Liu, C. et al. Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell. Stem. Cell. 6, 433–444 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Gao, Y. et al. Inhibition of miR-15a Promotes BDNF expression and rescues dendritic maturation deficits in MeCP2-deficient neurons. Stem Cells 33, 1618–1629 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Giresi, P. G., Kim, J., McDaniell, R. M., Iyer, V. R. & Lieb, J. D. FAIRE (Formaldehyde-assisted isolation of regulatory elements) isolates active regulatory elements from human chromatin. Genome Res. 17, 877–885 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Dagda, R. K. et al. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J. Biol. Chem. 284, 13843–13855 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Guo, W., Patzlaff, N. E., Jobe, E. M. & Zhao, X. Isolation of multipotent neural stem or progenitor cells from both the dentate gyrus and subventricular zone of a single adult mouse. Nat. Protoc. 7, 2005–2012 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Thomas, P. D. et al. PANTHER: a library of protein families and subfamilies indexed by function. Genome Res. 13, 2129–2141 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Zhang, B., Kirov, S. & Snoddy, J. WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res. 33, W741–W748 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Stark, C. et al. BioGRID: a general repository for interaction datasets. Nucleic Acids Res. 34, D535–D539 (2006).

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Guo, W. et al. RNA-binding protein FXR2 regulates adult hippocampal neurogenesis by reducing Noggin expression. Neuron 70, 924–938 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Zhang, M. et al. Rational design of true monomeric and bright photoactivatable fluorescent proteins. Nat. Methods 9, 727–729 (2012).

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Beckel-Mitchener, A. C., Miera, A., Keller, R. & Perrone-Bizzozero, N. I. Poly(A) tail length-dependent stabilization of GAP-43 mRNA by the RNA-binding protein HuD. J. Biol. Chem. 277, 27996–28002 (2002).

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Contestabile, A. et al. Lithium rescues synaptic plasticity and memory in Down syndrome mice. J. Clin. Invest. 123, 348–361 (2013).

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Gantois, I. et al. Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat. Med. 23, 674–677 (2017).

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Chambers, S. M. et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27, 275–280 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Guillaume, D. J., Johnson, M. A., Li, X. J. & Zhang, S. C. Human embryonic stem cell-derived neural precursors develop into neurons and integrate into the host brain. J. Neurosci. Res. 84, 1165–1176 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

We thank Y. Xing, S. Malone, H. Zhao, E. Berndt, Y. Zhao, J. Le, Y. Sun, J. Hoang, Y. Tao, J. Wang, and R. Spitzer for technical assistance; Q. Bu, A. Wang, Q. Chang, D. Joshi, S. Shapiro, and W. Qiu for help with mitochondrial analysis; K. Knobel, J. Pinnow, H. Mitchell at the Waisman IDD Model Core; UW Carbone Cancer Center Flow Cytometry lab for help with cell isolation; and S. Splinter-BonDurant and the UW-Madison Biotechnology Center for next generation sequencing services. We also thank U. Mueller (Scripps Institute, San Diego, CA) for Tg(Dcx -CreERT2) mice and D. Lie (Friedrich-Alexander University, Erlangen, Germany) and C. Chang for viral vectors expressing mitochondrial markers. This work was supported by grants from the National Institutes of Health (R01MH078972, R56MH113146, R01NS105200 and R01MH116582 to X.Z., P30HD03352, U54HD090256 to the Waisman Center, MH061876 and NS097362 to E.R.C., F32NS098604 to J.D.V.), UW Vilas Trust (Kellett Mid-Career Award) and UW-Madison and Wisconsin Alumni Research Foundation (to X.Z.), Jenni and Kyle Professorship (to X.Z.), John Merck Fund (to X.Z, and A.B)., and in part by the National Institute on Aging, Intramural Research Program (to H.v.P.).

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Contributions

X.Z. conceived and designed the project, approved the experimental plans, kept track of the project, wrote and submitted the manuscript. M.S. designed the experiments, collected and analyzed data for most figures, kept track of the progress of the project, wrote and submitted the manuscript. F.W. designed the experiments, collected and analyzed data in Fig. 1 and performed FACS-seq in Fig. 3. M.L. created sgRNA/dCas9 system and helped with bioinformatics analysis and human iPSC differentiation. M.E.S. collected some of the qPCR, western blotting and confocal microscopy data for phenotypic analysis of both mouse and human neurons. J.J.T. collected data for in vivo analysis in Fig. 1. T.K. performed quantitative analysis of most of the in vitro neuronal dendrites, S.K. collected data for retroviral-labeled neurons. Y.G. created retroviral and lentiviral Cre and shRNA constructs. N.S. and H.v.P. performed electrophysiological analysis. J.D.V. and E.R.C. analyzed mitochondria dynamics using live imaging. A.B. worked with M.S. in human iPSC differentiation and transplantation.

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Correspondence to Xinyu Zhao.

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Supplementary information

Supplementary Figures 1–25

Supplementary Figures 1–25

Reporting Summary

Supplementary Note

Information on antibodies.

Supplementary Table 1

DE genes in Fmr1-KO Dcx-DsRed neurons.

Supplementary Table 2

WebGestalt enrichment.

Supplementary Table 3

PANTHER GO analysis.

Supplementary Table 4

Shared targets among published FMRP targets.

Supplementary Table 5

Physical and genetic interactions among all mouse genes (Mus musculus Version 3.4.161) as determined by BIOGRID.

Supplementary Table 6

FMRP targets interacting with DE genes in KO.

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Shen, M., Wang, F., Li, M. et al. Reduced mitochondrial fusion and Huntingtin levels contribute to impaired dendritic maturation and behavioral deficits in Fmr1-mutant mice. Nat Neurosci 22, 386–400 (2019). https://doi.org/10.1038/s41593-019-0338-y

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