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综合征是由染色体7上的28个基因的从头删除造成的。WBS的认知能力的特征是精神障碍和异常的超社会性格，对社会参与的兴趣明显增加。相互重复与自闭症谱系障碍，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有力的证据，即WBS地区的基因或基因以剂量敏感的方式影响社会行为，并潜在地习得。但是，哪个基因介导完整的认知表型尚不清楚。部分缺失的大量证据表明，一个三个转录因子（GTF2I家族）的家族可能会介导认知能力。然而，可用情况并未区分它是单个基因，还是介导该基因座影响的GTF2I家族剂量的总体作用。此外，不管基因座中哪个基因可能是严重的，这些基因改变行为的实际机制尚不清楚。最近，已经观察到，携带该突变的个体具有较高的水平，在血液中循环的神经肽催产素（OXT），一个分子 众所周知，在包括人类在内的所有哺乳动物中，在束缚，社会互动和其他行为中都有角色。一种可能性是，GTF2I家庭成员的单倍不足会导致神经肽的合成增加，从而改变了社交驱动力。但是，该假设尚未在功能上进行检验，并且WBS基因座突变和OXT释放之间的任何细胞或分子中间体都是不确定的。在这里，我们旨在利用小鼠的创新新基因组编辑方法，以系统地解决GTF2I家庭成员中的单倍弥补，或者需要单独或结合使用，以介导失去基因座对哺乳动物社会行为的全部影响。我们还将检验以下假设：WBS基因座的这些基因的丧失或多基因缺失能够提高OXT水平，并且我们将使用遗传方法来测试WBS - 区域介导的社会行为变化的OXT信号传导。最后，我们将采用以发现驱动的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。