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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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.

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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.

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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.).

Author information

Author notes

    • Feifei Wang

    Present address: State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and Institutes of Brain Science, and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China

    • Henriette van Praag

    Present address: Department of Biomedical Science, Charles E. Schmidt College of Medicine; and Brain Institute, Florida Atlantic University, Jupiter, FL, USA


  1. Waisman Center, University of Wisconsin-Madison, Madison, WI, USA

    • Minjie Shen
    • , Feifei Wang
    • , Meng Li
    • , Michael E. Stockton
    • , Joseph J. Tidei
    • , Yu Gao
    • , Tomer Korabelnikov
    • , Sudharsan Kannan
    • , Anita Bhattacharyya
    •  & Xinyu Zhao
  2. Department of Neuroscience, University of Wisconsin-Madison, Madison, WI, USA

    • Minjie Shen
    • , Feifei Wang
    • , Meng Li
    • , Michael E. Stockton
    • , Joseph J. Tidei
    • , Yu Gao
    • , Tomer Korabelnikov
    • , Sudharsan Kannan
    • , Jason D. Vevea
    • , Edwin R. Chapman
    •  & Xinyu Zhao
  3. Neuroplasticity and Behavior Unit, National Institute on Aging, Baltimore, MD, USA

    • Nirnath Sah
    •  & Henriette van Praag
  4. Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI, USA

    • Jason D. Vevea
    •  & Edwin R. Chapman
  5. Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, USA

    • Anita Bhattacharyya


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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.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Xinyu Zhao.

Supplementary information

  1. Supplementary Figures 1–25

    Supplementary Figures 1–25

  2. Reporting Summary

  3. Supplementary Note

    Information on antibodies.

  4. Supplementary Table 1

    DE genes in Fmr1-KO Dcx-DsRed neurons.

  5. Supplementary Table 2

    WebGestalt enrichment.

  6. Supplementary Table 3

    PANTHER GO analysis.

  7. Supplementary Table 4

    Shared targets among published FMRP targets.

  8. Supplementary Table 5

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

  9. Supplementary Table 6

    FMRP targets interacting with DE genes in KO.

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