Studying the Molecular Mechanism of Foxp1/2 Function Controlling the Cerebellar Development

Foxp1/2功能控制小脑发育的分子机制研究

• 批准号: 10676978
• 负责人: Nagham Khouri Farah
• 金额: $ 4.42万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10676978
• 关键词: Address; Adult; Affect; Affinity; Animal Model; Ataxia; Attention; Automobile Driving; Bilateral; Binding; Biochemical; Biological Assay; Cell Differentiation process; Cells; Cellular Morphology; Cerebellar Cortex; Cerebellar Diseases; Cerebellar vermis structure; Cerebellum; Chromatin; Cognition Disorders; Cognitive; Collaborations; Communities; Competitive Binding; Connecticut; DNA Binding; DNA Sequence; Data; Data Analyses; Data Set; Development; Developmental Biology; Embryo; Enhancers; Equilibrium; Event; FOXP1 gene; FOXP2 gene; Foundations; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Transcription; Genomic Segment; Goals; Health; Heterogeneity; Homo; Image; Impairment; Individual; Knock-out; Knockout Mice; Language; Learning; Ligands; Light; Link; Mammals; Mental Retardation; Molecular; Morphogenesis; Morphology; Movement; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Neurosciences; Oral; Outcome; Perception; Population; Population Heterogeneity; Promoter Regions; Prosencephalon; Purkinje Cells; Role; Science; Scientist; Sensory; Signal Pathway; Signal Transduction; Solid; Specific qualifier value; Speech; Testing; Training; Universities; Writing; autism spectrum disorder; career; cell motility; cognitive function; combinatorial; differential expression; experience; experimental study; gene network; genome-wide; in vivo; insight; invention; language impairment; multiple omics; mutant; postnatal; preservation; prevent; receptor; responsible research conduct; single-cell RNA sequencing; transcription factor; transcriptome; transcriptomics

PROJECT SUMMARY/ABSTRACT Mutations of FOXP1 and FOXP2, which encode forkhead box transcription factors, are associated with autism, mental retardation and language impairment. Functional studies in animal models have demonstrated combinatorial roles of FoxPs in the development of the CNS, particularly the forebrain. However, a clear understanding about their functional mechanisms is lacking. We recently discovered that molecularly heterogeneous populations of Purkinje cells (PCs) express different combinations of Foxp1, 2 and 4 in the mouse embryonic cerebellum. Through cerebellum-specific knockout experiments, we showed that the loss of Foxp1 or Foxp2 impacted PC diversification. Strikingly, deleting both Foxp1 and 2 resulted in a total loss of the cerebellar hemisphere, which has evolved de novo in mammals and is involved in cognitive and language functions. Our long-term goal is to determine the molecular and cellular mechanisms underlying the assembly of cerebellar circuitry. We hypothesize that Foxp1 and Foxp2 cooperatively specify the molecular identity of PC groups that are crucial for cerebellar hemisphere formation and expansion. To address this hypothesis and contribute to our goal, we propose to: 1) use single-cell transcriptomics and light-sheet volume imaging to ascertain how Foxp1 and Foxp2 regulate PC differentiation and morphogenesis of the cerebellum, 2) determine genome-wide binding profiles of Foxp1 and Foxp2 in mutant and control cerebella. Integrative analysis of data generated from these aims will unravel the transcription network governed by the combinatorial function of Foxp1 and Foxp2 in the developing cerebellum. The proposed training plan is sponsored by Dr. Yuanhao James Li and Dr. Justin Cotney at the University of Connecticut Health Center. The overall goal of the training plan is to provide the PI, Ms. Nagham Khouri Farah, with a solid foundation for a successful career as an independent scientist. The training plan will help the PI gain experiences: 1) to conduct multi-omics experiments and analyses, 2) to responsibly conduct research, 3) to collaborate with other scientists, 4) to present data in a written and oral format, 5) to make a significant contribution to the science community in the field of genetics, neuroscience and developmental biology.

项目概要/摘要 编码叉头盒转录因子的 FOXP1 和 FOXP2 的突变与自闭症有关， 智力低下和语言障碍。动物模型的功能研究表明 FoxPs 在中枢神经系统（特别是前脑）发育中的组合作用。然而，一个明确的 缺乏对其功能机制的了解。我们最近发现，从分子角度 小鼠中浦肯野细胞 (PC) 的异质群体表达 Foxp1、2 和 4 的不同组合 胚胎小脑。通过小脑特异性敲除实验，我们发现 Foxp1 或 Foxp2 影响了 PC 的多元化。引人注目的是，同时删除 Foxp1 和 2 会导致小脑完全丧失 半球在哺乳动物中从头进化而来，参与认知和语言功能。我们的 长期目标是确定小脑组装的分子和细胞机制 电路。我们假设 Foxp1 和 Foxp2 共同指定 PC 基团的分子身份 这对于小脑半球的形成和扩张至关重要。为了解决这个假设并 为了实现我们的目标，我们建议：1）使用单细胞转录组学和光片体积成像 确定 Foxp1 和 Foxp2 如何调节 PC 分化和小脑形态发生，2) 确定 突变体和对照小脑中 Foxp1 和 Foxp2 的全基因组结合谱。数据综合分析 这些目标产生的结果将解开由 Foxp1 组合功能控制的转录网络 Foxp2 存在于发育中的小脑中。 拟议的培训计划由英国大学的Yuanhao James Li博士和Justin Cotney博士赞助 康涅狄格州健康中心。培训计划的总体目标是为 PI Nagham Khouri Farah 女士提供： 为独立科学家的成功职业生涯奠定了坚实的基础。培训计划将帮助PI获得 经验：1) 进行多组学实验和分析，2) 负责任地进行研究，3) 与其他科学家合作，4) 以书面和口头形式呈现数据，5) 做出重要的成果 在遗传学、神经科学和发育生物学领域对科学界的贡献。