Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioural and myelin alterations rescuable by a remyelinating drug [mouse P1]

Williams syndrome (WS), caused by a heterozygous microdeletion in 7q11.23, is a neurodevelopmental disorder characterized by hypersociability and neurocognitive abnormalities. Of the deleted genes, general transcription factor II-i (Gtf2i) has been linked to hypersociability in WS, though the underlying mechanisms are poorly understood. We show that selective deletion of Gtf2i in forebrain excitatory neurons caused neuroanatomical defects, fine motor deficits, increased sociability and anxiety. Unexpectedly, 70% of the genes with significantly decreased mRNA 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 behavioural deficits. Frontal cortex from WS patients 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. Whole cortex RNAseq of 1-day-old mutant and control mice.由7q11.23区域杂合性微缺失引发的威廉姆斯综合征（Williams syndrome, WS）是一类以过度社交倾向与神经认知异常为核心特征的神经发育障碍。在该病症相关的缺失基因中，通用转录因子II-i（general transcription factor II-i, Gtf2i）已被证实与WS患者的过度社交行为相关，但其潜在作用机制仍有待阐明。本研究发现，在前脑兴奋性神经元中选择性敲除Gtf2i，可导致小鼠出现神经解剖结构异常、精细运动障碍、社交行为亢进及焦虑样表型。出乎意料的是，突变小鼠皮层中mRNA水平显著下调的基因中有70%参与髓鞘形成过程；同时突变小鼠的成熟少突胶质细胞数量减少、髓鞘厚度降低，且轴突传导功能受损。通过氯马斯汀（clemastine）修复髓鞘形成功能，或提升轴突传导能力，均可有效挽救该模型小鼠的行为缺陷。威廉姆斯综合征患者的额叶皮层同样表现出髓鞘厚度降低、成熟少突胶质细胞数量减少，以及髓鞘形成相关基因的mRNA表达水平下调的特征。本研究为与神经元Gtf2i缺失相关的WS髓鞘形成缺陷提供了分子与细胞学层面的实验证据。本数据集涵盖1日龄突变型与野生型对照小鼠的全皮层RNA测序数据。