REGULATION OF MAMMALIAN SOCIAL BEHAVIOR BY THE GTF2I FAMILY OF PROTEINS

 描述（由申请人提供） Williams-Beuren综合征是由7号染色体上α ~28基因的复发性从头缺失引起的。WBS的认知特征是智力迟钝和不寻常的超社会人格，对社会参与的兴趣明显增加。相互复制与自闭症谱系障碍、分离焦虑和语言延迟有关。这些观察结果为以下假设提供了强有力的证据：WBS区域中的一个或多个基因以剂量敏感的方式影响社会行为和潜在的语言习得。然而，哪些基因介导完整的认知表型尚不清楚。来自部分缺失的优势证据表明3个转录因子家族（Gtf 2 i家族）可能介导认知特征。然而，现有的病例不能区分是否是单个基因或是否是Gtf 2 i家族剂量的整体效应介导了该位点的影响。此外，无论基因座中的哪个基因可能是致病基因，这些基因改变行为的实际机制尚不清楚。最近，已经观察到，携带这种突变的个体在血液中循环的神经肽催产素（Oxt）水平显著较高， 众所周知，它们在所有哺乳动物（包括人类）的配对、社会互动和其他行为中发挥作用。因此，一种可能性是Gtf 2 i家族成员的单倍不足导致神经肽合成增加，从而改变了社会驱动力。然而，这一假设尚未在功能上进行测试，并且WBS基因座突变和Oxt释放之间的任何细胞或分子中介都未定义。在这里，我们的目标是利用小鼠中创新的新基因组编辑方法，系统地解决Gtf 2 i家族成员中的单倍不足是否需要单独或组合来介导基因座丢失对哺乳动物社会行为的全面影响。我们还将测试这些基因单独缺失或WBS位点的多基因缺失能够增加Oxt水平的假设，并且我们将使用遗传方法来测试Oxt信号传导对WBS区域介导的社会行为改变的必要性。最后，我们将采取发现驱动和假设驱动的方法来定义这些突变在大脑中的分子和细胞后果。

 DESCRIPTION (provided by applicant) Williams-Beuren syndrome is caused by a recurrent de novo deletion of a ~28 genes on chromosome 7. The cognitive profile of WBS is characterized by mental retardation and an unusual hyper-social personality with a demonstrably increased interest in social engagement. The reciprocal duplication has been associated with autism spectrum disorder, separation anxiety, and language delay. These observations provide strong evidence for the hypothesis that a gene or genes in the WBS region influences social behavior, and potentially language acquisition, in a dosage sensitive manner. However, which gene(s) mediate the complete cognitive phenotype is not clear. The preponderance of evidence from partial deletions suggests a family of 3 transcription factors (the Gtf2i family) may mediate the cognitive profile. Yet the available cases do not distinguish whether it is individual genes or whether it is an overall effec of Gtf2i family dose that mediates the impact of the locus. Furthermore, regardless of which gene(s) in the locus may be causative, the actual mechanism by which these genes alter behavior is unclear. Recently, it has been observed that individuals harboring this mutation have significantly higher levels of the neuropeptide Oxytocin (Oxt) circulating in the blood, a molecule well known to have roles in pair-bonding, social interaction, and other behaviors across all mammals, including humans. Thus one possibility is that haploinsufficiency of Gtf2i family members leads to increased neuropeptide synthesis and thus altered social drive. However, this hypothesis has not been tested functionally and any cellular or molecular intermediaries between WBS loci mutations and Oxt release are undefined. Here, we aim to leverage innovative new genome editing approaches in mice to systematically address whether haploinsufficiency in Gtf2i family members individually, or in combination, is required to mediate the full impact of loss of the locus on social behavior in mammals. We will also test the hypothesis that loss of these genes individually, or multi-gene deletions of the WBS locus, are able to increase Oxt levels, and we will use genetic approaches to test the necessity of Oxt signaling for WBS-region mediated alterations in social behavior. Finally, we will take both discovery-driven and hypothesis-driven approaches to defining the molecular and cellular consequences of these mutations in the brain.