Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioral and myelin alterations rescuable by a remyelinating drug
Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioral and myelin alterations rescuable by a remyelinating drug
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DOI：
10.1038/s41593-019-0380-9
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发表时间：
2019-05-01
影响因子：
25
通讯作者：
Feng, Guoping
中科院分区：
文献类型：
--
作者：
Barak, Boaz;Zhang, Zicong;Feng, Guoping
威廉姆斯综合征(Williams综合征，WS)是由染色体7q11.23杂合性微缺失引起的以多社交和神经认知异常为特征的神经发育障碍。在缺失的基因中，通用转录因子III(Gtf2i)与WS的超社交性有关，尽管其潜在机制尚不清楚。我们发现，前脑兴奋性神经元中Gtf2i的选择性缺失会导致神经解剖缺陷、精细运动障碍、社交能力增强和焦虑。出乎意料的是，突变小鼠皮质中信使RNA水平显著下降的基因中有70%参与了髓鞘形成，突变小鼠成熟少突胶质细胞数量减少，髓鞘厚度减少，轴突传导性受损。用氯马斯汀恢复髓鞘形成特性或增加轴突电导率可以挽救行为缺陷。WS患者额叶皮质髓鞘厚度减少，成熟少突胶质细胞数量减少，髓鞘形成相关基因表达水平降低。我们的研究为WS的髓鞘缺陷提供了与神经元Gtf2i缺失有关的分子和细胞证据。
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.