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Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioral and myelin alterations rescuable by a remyelinating drug

Nature Neuroscience volume 22, pages 700–708 (2019)Cite this article

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A Publisher Correction to this article was published on 05 June 2019

Abstract

Williams syndrome (WS), caused by a heterozygous microdeletion on chromosome 7q11.23, is a neurodevelopmental disorder characterized by hypersociability and neurocognitive abnormalities. Of the deleted genes, general transcription factor IIi (Gtf2i) has been linked to hypersociability in WS, although the underlying mechanisms are poorly understood. We show that selective deletion of Gtf2i in the excitatory neurons of the forebrain caused neuroanatomical defects, fine motor deficits, increased sociability and anxiety. Unexpectedly, 70% of the genes with significantly decreased messenger RNA levels in the mutant mouse cortex are involved in myelination, and mutant mice had reduced mature oligodendrocyte cell numbers, reduced myelin thickness and impaired axonal conductivity. Restoring myelination properties with clemastine or increasing axonal conductivity rescued the behavioral deficits. The frontal cortex from patients with WS similarly showed reduced myelin thickness, mature oligodendrocyte cell numbers and mRNA levels of myelination-related genes. Our study provides molecular and cellular evidence for myelination deficits in WS linked to neuronal deletion of Gtf2i.

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Fig. 1: Neuroanatomical and behavioral deficits in Gtf2i cKO mice.
Fig. 2: Myelination-related transcriptomic and cellular alterations in Gtf2i cKO mice.
Fig. 3: Gtf2i cKO mice show impaired myelin ultrastructure, neuronal conductivity and motor skills.
Fig. 4: Gtf2i cKO mice impaired myelin-related properties are rescued following acute administration of 4-AP.
Fig. 5: The impaired myelin-related properties of Gtf2i cKO mice are rescued following chronic administration of clemastine.
Fig. 6: Myelination-related transcriptomic alterations in the frontal cortex of patients with WS.

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Data availability

All data are available in the main text or the supplementary materials. All RNA-Seq datasets generated and analyzed during the current study are available in the supplementary tables and from the corresponding author upon reasonable request. RNA data are available in the Gene Expression Omnibus (GEO) with accession code GSE128841. All data generated in this study are deposited in the GEO under accession code TBD.

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Acknowledgements

The authors gratefully acknowledge M.E. Greenberg for advice and guidance and E. Okun, P. Monteiro, A. Krol, J. Wilde, A. Marco and S. Alon for insightful comments on the manuscript. H. Zaniewski and J. Wang provided technical help. Human tissue was obtained from the NIH NeuroBioBank at the University of Maryland. We thank the donors of the brain tissue and their families for their invaluable donations for the advancement of scientific understanding. This work is supported by a grant from the Simons Foundation (grant no. SFARI 240005 to G.F.), the Tang-Yang Center for Autism Research at MIT, the Poitras Center for Psychiatric Disorders Research at MIT, the Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard and the Simons Center for the Social Brain at MIT. B.B. was supported by postdoctoral fellowships from the Simons Center for the Social Brain at MIT and the Autism Science Foundation.

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Authors and Affiliations

  1. McGovern Institute for Brain Research and Department of Brain & Cognitive Sciences, MIT, Cambridge, MA, USA

    Boaz Barak, Michaela Ennis, Dongqing Wang, Kathleen Quast & Guoping Feng

  2. The School of Psychological Sciences, Faculty of Social Sciences, Tel Aviv University, Tel Aviv, Israel

    Boaz Barak & Sari S. Trangle

  3. The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    Boaz Barak & Ariel Nir

  4. F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurology, Harvard Medical School, Boston, MA, USA

    Zicong Zhang, Yuanyuan Liu, Yi Li & Zhigang He

  5. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Kirsten M. Levandowski & Guoping Feng

  6. Department of Neurobiology, Harvard Medical School, Boston, MA, USA

    Gabriella L. Boulting

  7. Department of Reconstructive Sciences, University of Connecticut, Farmington, CT, USA

    Dashzeveg Bayarsaihan

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Contributions

B.B., Z.Z., Y.Liu., Z.H. and G.F. designed the experiments and wrote the manuscript. B.B. collected, analyzed and interpreted the results from studies related to behavior, biochemistry, genomics, immunofluorescence and pharmacology. M.E. collected and analyzed the results of immunofluorescence studies. Z.Z. collected, analyzed and interpreted the results from electrophysiological studies from the CST and corpus callosum. K.Q. collected, analyzed and interpreted the results from electrophysiological studies to characterize the properties of the basal membrane. K.M.L. collected and analyzed the results from the human immunostaining studies. Y.Liu collected, analyzed and interpreted the results from the fine motor skills and CST immunostaining studies. S.S.T. and A.N. collected, analyzed and interpreted the results from the clemastine study and the human immunofluorescence studies. D.W. administered the clemastine. Y.Li collected and analyzed the CST immunostaining studies. D.B. donated the Gtf2i loxP mice. B.B., G.L.B., Z.Z., Y.Liu, Z.H. and G.F. interpreted the results.

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Correspondence to Boaz Barak, Zhigang He or Guoping Feng.

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Barak, B., Zhang, Z., Liu, Y. et al. Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioral and myelin alterations rescuable by a remyelinating drug. Nat Neurosci 22, 700–708 (2019). https://doi.org/10.1038/s41593-019-0380-9

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