Extensive characterization of a Williams syndrome murine model shows Gtf2ird1-mediated rescue of select sensorimotor tasks, but no effect on enhanced social behavior.
Extensive characterization of a Williams syndrome murine model shows Gtf2ird1-mediated rescue of select sensorimotor tasks, but no effect on enhanced social behavior.
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DOI：
10.1111/gbb.12853
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发表时间：
2023-08
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影响因子：
--
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中科院分区：
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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，包括社交动机增加、焦虑和特定恐惧症的风险以及运动功能紊乱。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，它编码的转录因子被认为在威廉姆斯综合征的行为特征中发挥作用。整个区域的重复也会导致频繁的自闭症诊断、社交恐惧症和语言发育迟缓。因此，该区域的基因似乎以剂量敏感的方式调节社会动机。杂合地消除同线威廉姆斯综合征区域的“完全缺失”小鼠，已对心脏表型进行了深入的表征，但尚未评估社会动机的直接测量。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。在这里，我们生成了过度表达 Gtf2ird1 的小鼠，它既可用于单独模拟该基因的复制，也可用于挽救完全缺失小鼠中的 Gtf2ird1 表达。使用全面的行为管道和社会动机的直接测量，我们提供了证据，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 Gtf2ird1 互补不足以挽救大多数这些特征，并且重复不会降低社会动机。然而，Gtf2ird1 互补确实可以挽救特定感觉运动任务的光厌恶行为和表现，这可能表明该基因在感觉处理或整合中的作用。威廉姆斯综合征关键区 (WSCR) 的半合子缺失会导致广泛的行为差异，其中很少受 Gtf2ird1 影响。具体来说，WSCR 调节社会动机以及运动和焦虑表型，但 Gtf2ird1 互补不足以挽救大多数这些特征。然而，Gtf2ird1 互补确实可以挽救特定感觉运动任务的光厌恶行为和表现，这可能表明该基因在感觉处理或整合中的作用。
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. Hemizygous deletion of the Williams syndrome critical region (WSCR) causes widespread behavioral differences, few of which are affected by Gtf2ird1. Specifically, the WSCR regulates social motivation along with motor and anxiety phenotypes, but Gtf2ird1 complementation is not sufficient to rescue most of these traits. 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.
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影响因子：
2
作者：
Morris, Colleen A.;Mervis, Carolyn B.;Paciorkowski, Alex P.;Abdul-Rahman, Omar;Dugan, Sarah L.;Rope, Alan F.;Bader, Patricia;Hendon, Laura G.;Velleman, Shelley L.;Klein-Tasman, Bonita P.;Osborne, Lucy R.
通讯作者：
Osborne, Lucy R.
DOI：
10.1097/dbp.0000000000001068
发表时间：
2022-08-01
影响因子：
2.4
作者：
Klein-Tasman, Bonita P.;Yund, Brianna D.;Mervis, Carolyn B.
通讯作者：
Mervis, Carolyn B.
影响因子：
3.4
作者：
Maloney SE;Akula S;Rieger MA;McCullough KB;Chandler K;Corbett AM;McGowin AE;Dougherty JD
通讯作者：
Dougherty JD
影响因子：
81.5
作者：
Kozel, Beth A.;Barak, Boaz;Kim, Chong Ae;Mervis, Carolyn B.;Osborne, Lucy R.;Porter, Melanie;Pober, Barbara R.
通讯作者：
Pober, Barbara R.
影响因子：
9.9
作者：
Gothelf, D;Farber, N;Attias, J
通讯作者：
Attias, J