FoxG1-directed Gene network in forebrain development and FoxG1 syndrome

FoxG1主导的前脑发育和FoxG1综合征中的基因网络

• 批准号: 9486007
• 负责人: Soo-Kyung Lee
• 金额: $ 48.61万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9486007
• 关键词: Address; Alleles; Autistic Disorder; Axon; Behavior; Binding; Biochemical Genetics; Brain; Cells; Cerebral cortex; Cerebrum; Chromatin; Clinical; Cognition Disorders; Cognitive; Complex; Corpus Callosum; Defect; Development; Emotional; Epigenetic Process; Epilepsy; Etiology; FOXG1B gene; Forebrain Development; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Goals; High-Throughput Nucleotide Sequencing; Histone Deacetylation; Histones; Human; Impairment; Intellectual functioning disability; Language; Lead; Link; Logic; Mental disorders; Microcephaly; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Neocortex; Neurodevelopmental Disorder; Neurologic Deficit; Neuronal Differentiation; Neurons; NuRD complex; Nucleosomes; Output; Pathology; Process; Production; Prosencephalon; Proteomics; Regulator Genes; Rett Syndrome; Role; Seizures; Seminal; Specificity; Speech; Syndrome; Testing; Time; Variant; autism spectrum disorder; base; cell type; chromatin modification; chromatin remodeling; demethylation; dosage; forkhead protein; genome-wide; in vivo; insight; migration; nerve stem cell; neurogenesis; overexpression; programs; recruit; screening; self-renewal; social; transcription factor; transcriptome sequencing

Project Summary The cerebral cortex is responsible for higher cognitive and emotional functions, and has served as an ideal model to study CNS development due to enormous cellular complexity. Our long-term goal is to fully decode the genetic and epigenetic mechanisms by which transcription factors (TFs) and chromatin remodelers cooperate to regulate the cortex development and how disruption of such mechanisms leads to neurodevelopmental disorders with impaired cortical functions. To address these two critical issues, here we propose to study the role of the forkhead TF FoxG1 in corticogenesis and a human neurodevelopmental disorder FoxG1 syndrome (FS) (aka, a congenital variant of Rett syndrome, RTT), which results from inactivating mutations in one allele of the FoxG1 gene. Prominent clinical features of FS include microcephaly, agenesis of the corpus callosum, profound intellectual disability with autistic features and absent language, and seizures. Duplication of FoxG1 is also associated with developmental epilepsy, intellectual disability, and severe speech and social impairment. Overexpression of FoxG1 via unknown mechanism is also implicated in autism. These results indicate that brain development is highly sensitive to the dosage of FoxG1. The mechanisms underlying timely neurogenesis and production of diverse cortical neuronal types are beginning to be understood thanks to the discovery of TFs that are expressed with temporal and regional specificity within the neocortex. During CNS development, the neurogenic TFs are often expressed in multiple cell types, suggesting that neuronal TFs may acquire cell type-specific activity by regulating distinct sets of target genes in cell context-dependent manner. However, the molecular mechanisms by which neuronal TFs recognize and control cell type-specific transcription program in the developing cortex remain ill-defined. FoxG1 is strongly expressed in forebrain NPCs, in which it regulates self-renewal and a timing of neurogenesis. FoxG1 is downregulated during differentiation of NPCs, and then re-expressed in cortical neurons, in which FoxG1 promotes neuronal entry into the cortical plate (CP). While these results suggest cell context-dependent actions of FoxG1, the gene regulatory mechanisms by which FoxG1 controls the sequential steps of cortex development and how these mechanisms relate to FS pathology are unclear. Our unbiased comprehensive screening approaches (ChIPseq, RNAseq and proteomics) disclosed key clues for understanding the molecular actions of FoxG1 in the developing cortex. Based on these seminal findings, we hypothesize that FoxG1 regulates its target genes in a developmental timing sensitive manner by collaborating with cell type- specific partner TFs and chromatin regulatory factors in cortex development, and dysregulation of these processes leads to neurological deficits in FS. We will test this hypothesis using an ensemble of cellular, biochemical, genetic, and comprehensive genome-wide approaches.

项目摘要 大脑皮层负责更高的认知和情感功能，并作为一个理想的 模型来研究中枢神经系统的发展，由于巨大的细胞复杂性。我们的长期目标是完全解码 转录因子（TF）和染色质重塑者合作的遗传和表观遗传机制 调节皮质发育以及这种机制的破坏如何导致神经发育 皮质功能受损的疾病。为了解决这两个关键问题，我们建议研究 叉形头TF FoxG1在皮质生成和人类神经发育障碍FoxG1综合征中的作用 (FS)（又名，Rett综合征的先天性变体，RTT），由一个等位基因的失活突变引起 FoxG1基因FS的突出临床特征包括小头畸形，胼胝体发育不全， 严重的智力残疾，伴有自闭症特征和语言缺失，以及癫痫发作。FoxG1复制 还与发育性癫痫、智力残疾以及严重的言语和社交障碍有关。 FoxG1通过未知机制的过度表达也与自闭症有关。这些结果表明 大脑发育对FoxG1的剂量高度敏感。 及时的神经发生和不同皮质神经元类型的产生的机制是 由于发现了表达时间和区域的TF， 新皮层的特异性。在CNS发育过程中，神经源性TF通常以多种形式表达， 细胞类型，这表明神经元TF可能通过调节不同的细胞类型来获得细胞类型特异性活性。 以细胞环境依赖的方式靶向基因。然而，神经元TF的分子机制 在发育中的皮层中识别和控制细胞类型特异性转录程序仍然不清楚。 FoxG1在前脑NPC中强烈表达，在其中它调节自我更新和神经发生的时间。 FoxG1在NPC分化过程中下调，然后在皮质神经元中重新表达，其中 FoxG1促进神经元进入皮质板（CP）。虽然这些结果表明细胞环境依赖 FoxG1的作用，FoxG1控制皮质的顺序步骤的基因调控机制， 发展以及这些机制如何与FS病理学相关尚不清楚。我们公正全面的 筛选方法（ChIPseq，RNAseq和蛋白质组学）揭示了理解 FoxG1在大脑皮层发育中的分子作用基于这些开创性的发现，我们假设 FoxG1以发育时间敏感的方式调节其靶基因， 皮质发育中的特异性伴侣TF和染色质调节因子，以及这些因子的失调 过程导致FS的神经功能缺损。我们将使用一组细胞， 生物化学、遗传学和全面的全基因组方法。