REGULATION OF MAMMALIAN SOCIAL BEHAVIOR BY THE GTF2I FAMILY OF PROTEINS

GTF2I 蛋白质家族对哺乳动物社会行为的调节

• 批准号: 9444470
• 负责人: JOSEPH D DOUGHERTY
• 金额: $ 50.48万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-06 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9444470
• 关键词: 7q11.23; Address; Anatomy; Autistic Disorder; Behavior; Behavioral; Blood; Brain; Cardiac; Chromosomes; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 7; Cognitive; Disease; Dose; FKBP10 gene; Face; Family; Family member; GTF2I gene; Gene Expression; Genes; Heart Diseases; Human; Hypercalcemia; Individual; Language; Language Delays; Language Development; Mammals; Mediating; Mental Retardation; Molecular; Mus; Mutant Strains Mice; Mutation; Neurocognitive; Neuropeptides; Oxytocin; Pair Bond; Personality; Phenotype; Plasma; Protein Family; Recurrence; Regulation; Role; Separation Anxiety; Series; Signal Pathway; Signal Transduction; Social Behavior; Social Interaction; Statistical Data Interpretation; Stimulus; Symptoms; Synteny; Testing; Transcription Factor 3; Visuospatial; Williams Syndrome; analog; autism spectrum disorder; dosage; falls; genetic approach; genome editing; innovation; interest; mutant; novel; public health relevance; response; social; social engagement; transcription factor; transcriptome sequencing

 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.

 描述(由申请人提供) Williams-Beuren综合征是由7号染色体上a~28基因的反复缺失引起的。WBS的认知特征是智力低下和异常的高度社交人格，并明显增加了对社会参与的兴趣。这种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WBS区域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的假设提供了强有力的证据。然而，哪个基因(S)介导了完整的认知表型，目前还不清楚。部分缺失的证据表明，一个由3个转录因子家族(Gtf2i家族)组成的家族可能参与了认知模式的调节。然而，现有的病例没有区分是单个基因还是Gtf2i家族剂量的整体效应调节了该基因座的影响。此外，无论基因座上的哪个基因(S)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，人们观察到携带这种突变的个体血液中循环的神经肽催产素(Oxt)水平显著升高，这是一种分子。 众所周知，它在包括人类在内的所有哺乳动物的配对结合、社会互动和其他行为中都扮演着重要角色。因此，一种可能性是Gtf2i家族成员的单倍体不足导致神经肽合成增加，从而改变社会动力。然而，这一假设还没有得到功能上的检验，WBS基因突变和oxt释放之间的任何细胞或分子中介也是未知的。在这里，我们的目标是在小鼠中利用创新的新基因组编辑方法来系统地解决Gtf2i家族成员的单倍体不足是否需要单独或组合来调节该基因座丢失对哺乳动物社会行为的全面影响。我们还将测试假设，即这些基因单独丢失，或WBS基因座的多个基因缺失，能够增加OXT水平，我们将使用遗传学方法来测试WBS区域介导的社会行为变化中OXT信号的必要性。最后，我们将采用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。