威廉姆斯综合征是一种罕见的神经发育障碍,表现出认知和行为异常,包括增加社会动机,焦虑和特定恐惧症以及运动功能紊乱的风险。威廉姆斯综合征是由7号染色体上26-28个基因的微缺失引起的,其中包括GTF2IRD1,该基因编码一种转录因子,表明该转录因子在威廉姆斯综合征的行为特征中起作用。整个地区的重复也导致频繁的自闭症诊断,社交恐惧症和语言延迟。因此,该地区的基因似乎以剂量敏感的方式调节社会动机。一个“完全删除”鼠标,杂合地消除同势威廉姆斯综合征区域,已经被深度表征为心脏表型,但对社会动机的直接衡量尚未进行评估。此外,Gtf2ird1在这些行为中的作用尚未在相关的遗传背景下得到解决。这里,我们已经产生了过表达Gtf2ird1的小鼠,该小鼠可用于单独建立该基因的复制模型,并在完全缺失小鼠中挽救Gtf2ird1的表达。使用全面的行为管道和直接的社会动机衡量标准,我们提供的证据表明,威廉姆斯综合征关键区域调节社会动机以及运动和焦虑表型,但是Gtf2ird1互补不足以挽救大多数这些特征,重复不会降低社会动机。然而,Gtf2ird1互补可以挽救某些感觉运动任务中的光线厌恶行为和性能,也许表明该基因在感觉加工或整合中的作用。
Williams syndrome is a rare neurodevelopmental disorder exhibiting cognitive and behavioral abnormalities, including increased social motivation, risk of anxiety and specific phobias along with perturbed motor function. Williams syndrome is caused by a microdeletion of 26-28 genes on chromosome 7, including
GTF2IRD1, which encodes a transcription factor suggested to play a role in the behavioral profile of Williams syndrome. Duplications of the full region also lead to frequent autism diagnosis, social phobias and language delay. Thus, genes in the region appear to regulate social motivation in a dose-sensitive manner. A \"complete deletion\" mouse, heterozygously eliminating the syntenic Williams syndrome region, has been deeply characterized for cardiac phenotypes, but direct measures of social motivation have not been assessed. Furthermore, the role of
Gtf2ird1 in these behaviors has not been addressed in a relevant genetic context. Here, we have generated a mouse overexpressing
Gtf2ird1, which can be used both to model duplication of this gene alone and to rescue
Gtf2ird1 expression in the complete deletion mice. Using a comprehensive behavioral pipeline and direct measures of social motivation, we provide evidence that the Williams syndrome critical region regulates social motivation along with motor and anxiety phenotypes, but that Gtf2ird1 complementation is not sufficient to rescue most of these traits, and duplication does not decrease social motivation. However,
Gtf2ird1 complementation does rescue light-aversive behavior and performance on select sensorimotor tasks, perhaps indicating a role for this gene in sensory processing or integration.