Molecular and Behavioral Neurobiology of Transcription Factor TCF4

转录因子 TCF4 的分子和行为神经生物学

基本信息

批准号：
8883724
负责人：
John David Sweatt
金额：
$ 36.75万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8883724
关键词：
Accounting Acetylesterase Acute Address Adult Alleles Anatomy Area Auditory Autistic Disorder BHLH Protein Behavior Behavioral Binding Bioinformatics Boxing Brain Breeding Categories Chromatin Structure Cognition Cognitive Complex Coupled DNA DNA Methylation Dendritic Spines Development Diagnosis Epigenetic Process Etiology Exhibits Exons Family Gene Targeting Genes Genetic Genetic Engineering Genetic Transcription Genetically Engineered Mouse Genomics Health Hippocampus (Brain)Histone Deacetylase Histone Deacetylase Inhibitor Histones Homo Human Impaired cognition Introns Knock-out Laboratories Language Language Development Learning Long-Term Potentiation Mediating Memory Memory impairment Messenger RNA Modeling Molecular Molecular Biology Motor Mus Mutation Nervous System Physiology Neuraxis Neurobiology Neurons Patients Pharmaceutical Preparations Pharmacotherapy Physiological Predisposition Prosencephalon Proteins Regulation Regulatory Element Resources Role Route Schizophrenia Small RNA Social Behavior Social Interaction Susceptibility Gene Synapses Synaptic plasticity Syndrome TCF7L2 gene Testing Transcription factor genes Transcriptional Activation Transcriptional Regulation Veins Virus attenuation autistic behaviour base calmodulin-dependent protein kinase II cognitive function epigenomics experience gene function genetic risk factor genome wide association study improved in vivo inhibitor/antagonist innovation learned behavior loss of function mouse model next generation sequencing novel promoter response social communication synaptic function transcription factor transcriptome sequencing transcriptomics

项目摘要

DESCRIPTION (provided by applicant): The basic helix-loop-helix transcription factor TCF4 (aka E2-2) has been implicated broadly in human CNS function. TCF4 was confirmed in several large GWAS studies as one of the rare highly replicated schizophrenia susceptibility genes, and when haplo-insufficient TCF4 is the causative factor for Pitt-Hopkins Syndrome (PTHS). PTHS has compelling attributes in terms of human cognitive function, being associated with pronounced memory deficits, autistic behaviors, and importantly an almost complete lack of language development. Thus, understanding the roles and function of TCF4 in the CNS is highly significant with respect to human language and auditory cognition, memory function, autism spectrum behavior, and schizophrenia susceptibility. Despite the clear importance of TCF4 function in the human CNS, the basic neurobiology of TCF4 has been only sparsely studied. Thus, this Project will use genetically engineered mouse models to assess the role of TCF4 in memory, social interactions and communication, hippocampal synaptic plasticity, synaptic anatomy, and epigenomic and transcriptional regulation in the CNS. The central hypothesis of the proposed studies is that TCF4 regulates the brain's ability to trigger long-term synaptic plasticity and memory formation by actively regulating transcriptional activity in response to behavioral experience. The approach will be to use both germline constitutive knockout and acute knockdown or deletion of TCF4 in the adult mouse hippocampus, coupled with extensive behavioral, electrophysiological, and transcriptomic/epigenomic characterization, to determine if TCF4 function is necessary in an ongoing fashion for normal memory and synaptic plasticity in the mature CNS. The studies will capitalize not only upon the available germline knockout line but also upon an already-available floxed TCF4 allele mouse line, and combine these mice with both virus- driven cre expression in the adult hippocampus and post-developmental CaMKII promoter-driven forebrain neuron-selective cre expression to achieve inducible post-developmental attenuation of CNS TCF4 function in vivo. Using these novel mouse models we will undertake three Specific Aims. Aim 1 will test the hypothesis that TCF4-deficient mice exhibit cognitive memory and social interaction deficits, and also test the hypothesis that TCF4-deficient mice exhibit altered synaptic plasticity. Aim 2 will comprise a significant translational component of the studies and will test the hypothesis that transcription-promoting Histone DeAcetylase Inhibitors (HDACi) will restore learning, memory, and synaptic plasticity in TCF4-deficient mice, as proof-of- concept that behavioral deficits and plasticity deficits in PTHS model mice can be reversed pharmacologically with HDACi. Aim 3 will test the hypothesis that loss of TCF4 function triggers secondary alterations in chromatin structure, DNA methylation, and gene transcription in the mature CNS. Toward this end, we will use the unbiased approach of utilizing MBD-seq, mRNA-seq, and small RNA-seq approaches for a comprehensive analysis of potential transcriptomic and epigenomic alterations in TCF4-deficient mice.

描述（由申请人提供）：基本的Helix-Loop-helix转录因子TCF4（又名E2-2）已广泛涉及人类CNS功能。在几项大型GWAS研究中证实了TCF4是罕见的高度复制的精神分裂症易感性基因之一，而当单倍不使它无效的TCF4是Pitt-Hopkins综合征（PTHS）的病因时。 PTHS在人类的认知功能方面具有引人注目的属性，与明显的记忆缺陷，自闭症行为相关联，重要的是几乎完全缺乏语言发展。因此，了解TCF4在中枢神经系统中的作用和功能在人类语言和听觉认知，记忆功能，自闭症频谱行为和精神分裂症敏感性方面非常重要。尽管TCF4功能在人类中枢神经系统中具有明显的重要性，但仅研究了TCF4的基本神经生物学。因此，该项目将使用基因工程的小鼠模型来评估TCF4在记忆，社交相互作用和交流中的作用，海马突触可塑性，突触解剖结构以及CNS中的表观基因组和转录调节。提出的研究的中心假设是，TCF4通过响应行为经验来主动调节转录活性来调节大脑触发长期突触可塑性和记忆形成的能力。该方法将是使用成年小鼠海马中的种系本链量基敲除和TCF4的急性敲除或删除TCF4，并与广泛的行为，电生理学和表征/表观基因组学表征相结合，以确定TCF4功能是否在正常记忆和突发性中的正常记忆和Mature contaps protination中是必要的。 The studies will capitalize not only upon the available germline knockout line but also upon an already-available floxed TCF4 allele mouse line, and combine these mice with both virus- driven cre expression in the adult hippocampus and post-developmental CaMKII promoter-driven forebrain neuron-selective cre expression to achieve inducible post-developmental attenuation of CNS TCF4 function in vivo.使用这些新型鼠标模型，我们将实现三个特定目标。 AIM 1将检验以下假设：TCF4缺陷型小鼠表现出认知记忆和社交相互作用缺陷，并测试了TCF4缺陷小鼠表现出改变的突触可塑性的假设。 AIM 2将构成重大的翻译研究的组成部分，并将检验以下假设：转录促进组蛋白脱乙酰基酶抑制剂（HDACI）将恢复TCF4缺陷小鼠中的学习，记忆和突触可塑性，作为PTHS模型中行为缺陷和可变性缺陷的概念证明可以用HDACI在药理学上逆转小鼠。 AIM 3将检验以下假设：TCF4功能的丧失会触发成熟CNS中染色质结构，DNA甲基化和基因转录的次要变化。为此，我们将使用公正的方法来利用MBD-Seq，mRNA-Seq和小的RNA-Seq方法，对TCF4缺陷型小鼠的潜在转录组和表观基因组改变的全面分析。