Genetic Control of Basal Telencephalic Development

基础端脑发育的遗传控制

• 批准号: 10297845
• 负责人: JOHN L. R. RUBENSTEIN
• 金额: $ 59.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-20 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10297845
• 关键词: ATAC-seq; Age; Automobile Driving; Basal Ganglia; Binding; Binding Sites; Brain region; Cells; Cerebral Palsy; Cerebral cortex; ChIP-seq; Code; Cognition; Data; Development; Dorsal; Emotions; Epilepsy; Foundations; Functional disorder; Ganglia; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Genomic Segment; Genomics; Heterogeneity; Histones; Informatics; Interneurons; Label; Location; Maps; Medial; Methods; Modeling; Molecular; Movement; Mus; Mutant Strains Mice; Neurons; Parvalbumins; Pathway interactions; Population; Regulatory Element; Role; Schizophrenia; Somatostatin; Specific qualifier value; Testing; Time; Ventricular; autism spectrum disorder; cell type; cortex mapping; differential expression; epigenome; epigenomics; experimental study; gene function; genome-wide; in vivo; mutant; network dysfunction; neuron development; neuropsychiatric disorder; novel; predictive test; progenitor; subventricular zone; transcription factor; transcriptome; transcriptome sequencing; transcriptomics

Telencephalic GABAergic neurons have central roles in cognition, movement and emotion. Dysfunction of these neurons is implicated in epilepsy, intellectual deficiency, autism and schizophrenia. During development, medial ganglionic eminence (MGE) progenitors generate a diversity of GABAergic neurons including Somatostatin (SST+) and Parvalbumin (PV+) cortical interneurons (CINs), and basal ganglia projection neurons. The identities of MGE-derived neurons are determined by the location within the MGE progenitor domain where they are specified, and the time during development when they are produced. Understanding the transcriptional networks that govern spatial and temporal specification is crucial for determining the basic mechanisms of telencephalic GABAergic development, and how dysfunction of these networks can contribute to neuropsychiatric disorders. To elucidate the transcriptional networks driving the development of MGE progenitors and their derivatives, we must define the transcription factors (TFs) and regulatory elements (REs) involved, as well as the coding regions that they control. We hypothesize that spatially and temporally specific transcriptional circuits control telencephalic GABAergic neuron diversity. We propose a combination of genetic and genomic experiments in mice aimed at elucidating the networks of TFs that regulate the development of neurons generated in the MGE. Our approach leverages genetic labeling to selectively purify and manipulate specific MGE lineages, which will allow us to integrate transcriptomic and epigenomic data. We will define RNA expression in different MGE regions and at different ages using novel temporally-inducible CreER lines whose activities are regionally specific (Aim 1). We will then use Histone ChIP-Seq and ATAC-Seq to identify genomic regions (candidate REs) that have spatially and temporally dynamic epigenomic states; we will also use TF ChIP-Seq to identify in vivo binding sites for COUPTF1/2 and MAF/MAFB (Aim 2). From these data, we will begin to uncover the transcriptional circuits controlling MGE specification. The circuit models will be tested using mouse mutants that lack COUPTF1/2 and MAF/MAFB, TFs that we hypothesize regulate GABAergic neuron diversity in a temporal- and spatial- dependent manner (Aim 3 & 4). Elucidating transcription circuits driving telencephalic GABAergic development provides a fundamental framework for understanding the genetic pathways, including the REs, that generate GABAergic neuron diversity and that may be dysregulated in neuropsychiatric disorders.

端脑GABA能神经元在认知、运动和情感中发挥核心作用。功能障碍 这些神经元与癫痫、智力缺陷、自闭症和精神分裂症有关。在开发过程中， 内侧神经节隆起（MGE）祖细胞产生多种GABA能神经元，包括 生长抑素（SST+）和小清蛋白（PV+）皮质中间神经元（CIN）和基底节投射 神经元MGE衍生神经元的身份由MGE祖细胞内的位置决定 指定它们的域以及它们生成时的开发时间。理解 控制空间和时间规范的转录网络对于确定基本的 端脑GABA能发育的机制，以及这些网络的功能障碍如何有助于 神经精神紊乱阐明推动MGE发展的转录网络 为了研究造血祖细胞及其衍生物，我们必须定义转录因子（TF）和调控元件（RE） 以及它们控制的编码区。 我们假设，空间和时间特异性转录回路控制端脑 GABA能神经元多样性。我们建议在小鼠中进行遗传和基因组实验， 阐明调节MGE中产生的神经元发育的TF网络。我们的方法 利用遗传标记来选择性地纯化和操纵特定的MGE谱系，这将使我们能够 整合转录组和表观基因组数据。我们将在不同的MGE区域定义RNA表达， 使用新的时间诱导型CreER系，其活性是区域特异性的（目的1）。我们 然后，将使用组蛋白ChIP-Seq和ATAC-Seq来鉴定在空间上具有以下特征的基因组区域（候选RE）： 和时间动态表观基因组状态;我们还将使用TF ChIP-Seq来鉴定体内结合位点， COUPTF 1/2和MAF/MAFB（目标2）。从这些数据中，我们将开始揭示转录回路 控制MGE规范。将使用缺乏COUPTF 1/2的小鼠突变体测试电路模型 和MAF/MAFB，我们假设TF在时间和空间上调节GABA能神经元的多样性， 依赖方式（目标3和4）。阐明驱动端脑GABA能发育的转录电路 提供了一个基本的框架，了解遗传途径，包括RE，产生 GABA能神经元的多样性和可能在神经精神疾病中失调。