Understanding the developmental progression of subpallial neural progenitor cells

了解大脑皮层下神经祖细胞的发育进程

• 批准号: 10659139
• 负责人: Xinwei Cao
• 金额: $ 44.88万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659139
• 关键词: Affect; Amygdaloid structure; Apical; Basal Ganglia; Binding; Bioinformatics; Biological; Biological Assay; Brain; Cell Count; Cell model; Cells; Chromatin; Complement; Complex; Critical Pathways; DNA Binding; DNA Binding Domain; Data Set; Development; Dissection; Drug Addiction; Embryo; Enhancers; Exhibits; Genes; Genetic; Genetic Transcription; Histologic; Homeostasis; In Situ; In Situ Hybridization; Interneurons; Knock-out; Knockout Mice; Knowledge; Ligation; Mammals; Medial; Mediating; Molecular; Multipotent Stem Cells; Natural regeneration; Neuroglia; Neurons; Organ; Orthologous Gene; Output; Pathway interactions; Pattern; Phenotype; Population; Property; Repression; Research; Role; Schizophrenia; Signal Pathway; Source; Specificity; Structure; Telencephalon; Testing; Tissues; Transcription Coactivator; Transcriptional Regulation; autism spectrum disorder; cell type; clinically relevant; cofactor; combinatorial; comparative; conditional knockout; data integration; fly; improved; in vivo; insulinoma associated 1; molecular marker; mouse model; nerve stem cell; nervous system disorder; nestin protein; neurodevelopment; neurogenesis; neuropsychiatric disorder; novel; progenitor; single-cell RNA sequencing; synergism; transcription factor; transcriptome sequencing; tumorigenesis

Project Summary The embryonic ventral telencephalon, the subpallium, is the developmental origin of numerous brain structures and cell populations such as the basal ganglia and cortical interneurons. These structures and cell populations are critical for higher brain functions and are often causally involved in neuropsychiatric disorders such as schizophrenia, autism, and drug addiction. Thus, a better understanding of ventral telencephalon development will not only improve our understanding of brain development and brain function but also advance treatments of nervous system disorders. All neurons and glia generated in the ventral telencephalon are descendants of subpallial neural progenitor cells (NPCs), which here broadly include multipotent stem/progenitor cells known as apical progenitors (APs) and lineage-restricted transit-amplifying cells known as basal or intermediate progenitors (BPs). Because research on NPCs during mammalian brain development has focused on the cortex, comparatively little is known about the steps of the developmental progression of subpallial NPCs and the mechanisms involved, although it is evident that subpallial NPCs must possess unique features that underlie their distinct cellular outputs (in terms of cell number and cell type). The objective of this application is to investigate the cellular and molecular mechanisms that control the developmental progression of subpallial NPCs. Recently, by analyzing a conditional knockout mouse line lacking Tead1 and Tead2, which encode key transcription factors of the Hippo pathway—a signaling pathway crucial for the development, tumorigenesis, and regeneration of most tissues across species, we found that the TEAD transcription factors are novel regulators of the developmental progression of subpallial NPCs; they uniquely regulate subpallial, but not pallial (cortical), NPCs and act through Hippo pathway-dependent and -independent mechanisms. The central hypothesis of this proposal is that TEAD regulates the developmental progression of subpallial NPCs with a dual mode of action: in APs, TEAD interacts with YAP/TAZ to maintain the AP state; in BPs, however, TEAD interacts with INSM1 to repress the AP state and promote developmental progression. Specifically, the proposed study will: (1) dissect the role of TEAD in subpallium development by using various genetic modified mouse models, (2) determine whether TEAD acts through INSM1 in subpallial basal progenitors, and (3) define the transcriptional mechanism through which TEAD regulates subpallial NPCs. The proposed study is expected to expand our knowledge of the mechanisms that uniquely regulate the developmental progression of subpallial NPCs and improve our understanding of an important signaling pathway—the Hippo pathway.

项目摘要 胚胎的腹侧端脑，即大脑皮层下，是许多大脑结构的发育起源。 以及基底节和皮质中间神经元等细胞群。这些结构和细胞群 对更高的大脑功能至关重要，并经常与神经精神障碍有关，如 精神分裂症、自闭症和毒瘾。因此，更好地了解腹侧端脑的发育 不仅会提高我们对大脑发育和大脑功能的了解，还会促进治疗 神经系统紊乱的症状。腹侧端脑产生的所有神经元和神经胶质细胞都是 大脑皮层下神经前体细胞(NPC)，这里广泛地包括已知的多潜能干细胞/祖细胞 作为顶端祖细胞(AP)和血统受限的转运放大细胞，称为基础或中间细胞 祖细胞(BPS)。因为对哺乳动物大脑发育过程中的神经前体细胞的研究主要集中在 大脑皮层，相对较少知道的发育进程的步骤下，神经前体细胞和 所涉及的机制，尽管很明显，大脑皮层下的NPC必须具有独特的特征， 是它们不同的细胞输出(细胞数量和细胞类型)的基础。此应用程序的目标是 探讨控制苍白球以下发育进程的细胞和分子机制 Npc。最近，通过分析缺少编码密钥的Tead1和Tead2的条件性基因敲除鼠系 河马途径的转录因子-一个在发育，肿瘤发生， 和大多数组织跨物种的再生，我们发现tead转录因子是新的 大脑皮层下鼻咽癌发育进程的调节者；它们独特地调节大脑皮层下，但不是 前庭(皮质)、NPC和通过河马通路依赖和非依赖机制起作用。中环 这一建议的假设是TEAD通过一种信号转导通路调节大脑皮质下鼻咽癌的发育进程。 双重动作模式：在AP中，TEAD与YAP/TAZ交互以维持AP状态；然而，在BPS中，TEAD 与INSM1相互作用，抑制AP状态，促进发育进程。具体地说， 拟议的研究将：(1)通过使用不同的遗传修饰来剖析TEAD在大脑皮层下发育中的作用 小鼠模型，(2)确定TEAD是否通过苍白质下基底祖细胞中的INSM1起作用，以及(3)定义 TEAD调控亚苍白质npc的转录机制。建议的研究是 希望扩大我们对独一无二的调节儿童发育过程的机制的了解 大脑皮层下的鼻咽癌细胞和提高我们对一个重要的信号通路-河马通路的理解。