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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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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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.
The authors declare no competing interests.
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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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