Genetic Studies of Cortex Structure and Development

皮层结构和发育的遗传学研究

• 批准号: 10684843
• 负责人: JOHN L. R. RUBENSTEIN
• 金额: $ 65.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684843
• 关键词: ATAC-seq; Alleles; Automobile Driving; Binding; Biological Assay; Cerebral cortex; ChIP-seq; Chromatin Remodeling Factor; Code; Development; Diagnosis; Enhancers; Epilepsy; Etiology; Genes; Genetic; Genetic Transcription; Genetic study; Genomics; Hippocampus; Histone H3; Histones; Human; Human Genetics; Lysine; Mental deficiency; Mus; Mutation; Neuronal Differentiation; Neurons; Pattern; Persons; Prosencephalon; Regulation; Regulatory Element; Research; Risk; Role; Schizophrenia; Signal Transduction; Specific qualifier value; Structure; Testing; Transgenic Mice; Transgenic Organisms; Untranslated RNA; Ventricular; Work; autism spectrum disorder; cell cortex; cell type; conditional mutant; disorder risk; epigenomic profiling; epigenomics; gene network; genetic information; genetic variant; human disease; in vivo; insight; neuropsychiatric disorder; novel; progenitor; promoter; spatiotemporal; subventricular zone; transcription factor; transmission process

PROJECT SUMMARY (30 lines) Dysregulation of cortical development is central to epilepsy, mental deficiency, autism and schizophrenia. Cortical progenitors generate the projection neurons of the cerebral cortex and hippocampus. Understanding the genetic circuitry controlling the development and function of the cortex is essential to interpret human allele variants in people who have neuropsychiatric disorders. To elucidate the genetic circuitry driving the development of cortical progenitors and neurons, we must define the essential transcription factors (TF), regulatory elements (REs) and coding regions. The proposed research on cortical regionalization and laminar specification, will overcome these barriers through the identification and functional characterization of REs implicated in cortical development. Further, the regulation of REs by chromatin modifiers is critical to their appropriate spatiotemporal activity8,9. Here we propose to make inroads into these subjects. We aim to elucidate transcriptional mechanisms through which patterning of cortical progenitors is transmitted to, and maintained in, cortical neurons. In this proposal, we will study TFs and their targets (putative REs or pREs) regulating cortical patterning and lamination (Aim 1). We will profile the regional and laminar epigenomic states of pREs using purified cortical progenitors and differentiating neurons (Aims 2 & 3). We will define the activity and function of pREs using transgenic mice and enhancer deletions (Aim 4). Finally, to define the function of chromatin modifiers in cortical regionalization and lamination, we will study a chromatin modifier conditional mutant (Kdm6b cKO, Aim 5). The proposed studies shift our research from the function of single genes towards understanding how transcriptional networks orchestrate cortical development. We will integrate, our collaborative large-scale genomics analyses of forebrain pREs1,43,44, with our ChIP-Seq (Chromatin Immunoprecipitation-Sequencing) analyses, to identify regional and laminar specific cortical pREs. This information can lead to insights about human disease alleles in non-coding sequences. Moreover, our results will provide critical information about the genetic control of cortical progenitors and neurons. Once integrated with human genetic information, this will lead to insights into how abnormalities in specific gene networks cause human neuropsychiatric disorders; insights that are essential for understanding etiology, diagnosis and perhaps treatment. For instance, mutations in Tbr1 increase autism risk40. Tbr1 encodes a TF that we discovered and functionally characterized2,3,13,38,41,42. We hypothesize that the work proposed herein will identify multiple novel putative REs (pREs), including for Tbr1, that control cortical development, and will be helpful to human geneticists to define the function of non-coding mutations that contribute to disease risk.

项目摘要（30行） 皮质发育的失调对于癫痫，精神缺乏，自闭症和精神分裂症至关重要。 皮质祖细胞产生大脑皮层和海马的投射神经元。理解 控制皮质的发育和功能的遗传回路对于解释人类等位基因至关重要 患有神经精神疾病的人的变体。阐明驱动遗传回路 皮质祖细胞和神经元的发展，我们必须定义基本转录因子（TF）， 监管要素（RES）和编码区域。拟议的关于皮质区域化和层流的研究 规范将通过res的识别和功能表征克服这些障碍 与皮质发育有关。此外，通过染色质修饰剂对RES的调节对于它们的调节至关重要 适当的时空活动8,9。在这里，我们建议融入这些主题。我们的目标 阐明转录机制，通过这些机制将皮质祖细胞的图案传播到，并 保持在皮质神经元中。 在此提案中，我们将研究TFS及其目标（推定的RES或PRES）调节皮质模式 和层压（目标1）。我们将使用纯化的PRES的区域和层状表观基因组态介绍 皮质祖细胞和区分神经元（目标2和3）。我们将定义PRES的活动和功能 使用转基因小鼠和增强子缺失（AIM 4）。最后，定义染色质修饰符的功能 皮质区域化和层压，我们将研究染色质修饰剂条件突变体（KDM6B CKO，AIM 5）。 拟议的研究将我们的研究从单个基因的功能转移到了解如何 转录网络协调皮质发展。我们将整合我们的合作大规模 前脑的基因组学分析1,43,44，我们的ChIP-Seq（染色质免疫沉淀 - 测序） 分析，以识别区域和层状特异性皮质Pres。这些信息可能会导致有关 非编码序列中的人类疾病等位基因。此外，我们的结果将提供有关的关键信息 皮质祖细胞和神经元的遗传控制。一旦与人类遗传信息整合在一起， 将导致人们对特定基因网络中异常的洞察力引起人类神经精神疾病； 对于理解病因，诊断和可能治疗至关重要的见解。例如， TBR1中的突变会增加自闭症风险40。 TBR1编码我们发现并在功能上发现的TF 特征为2,3,13,38,41,42。我们假设本文提出的工作将确定多个新颖的假定res （PRES），包括用于控制皮质发育的TBR1，将有助于人类遗传学家定义 有助于疾病风险的非编码突变的功能。

项目成果

Constructing and optimizing 3D atlases from 2D data with application to the developing mouse brain.

• DOI: 10.7554/elife.61408
• 发表时间: 2021-02-11
• 期刊: eLife
• 影响因子: 7.7
• 作者: Young DM;Fazel Darbandi S;Schwartz G;Bonzell Z;Yuruk D;Nojima M;Gole LC;Rubenstein JL;Yu W;Sanders SJ
• 通讯作者: Sanders SJ