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

Autor: Boaz, Barak, Zicong, Zhang, Yuanyuan, Liu, Ariel, Nir, Sari S, Trangle, Michaela, Ennis, Kirsten M, Levandowski, Dongqing, Wang, Kathleen, Quast, Gabriella L, Boulting, Yi, Li, Dashzeveg, Bayarsaihan, Zhigang, He, Guoping, Feng
Rok vydání: 2018
Předmět:
Zdroj: Nature neuroscience. 22(5)
ISSN: 1546-1726
Popis: 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.
Databáze: OpenAIRE
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