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

基本信息

批准号：
10459286
负责人：
Nagham Khouri Farah
金额：
$ 4.25万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
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/10459286
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 Communities Competitive Binding Connecticut DNA Binding DNA Sequence Data Data Analyses Data Set Development Developmental Biology Disease 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 Language Learning Ligands Light Link Mammals Mental Retardation Molecular Morphogenesis Morphology Movement Mus Mutation 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 Stains Testing Training Universities autism spectrum disorder base 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

项目摘要

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.

项目摘要/摘要编码叉子盒转录因子的FOXP1和FOXP2的突变与自闭症有关，智力低下和语言障碍。动物模型中的功能研究表明 FOXP在中枢神经系统的发展中的作用，尤其是前脑。但是，很清楚缺乏了解其功能机制。我们最近发现了分子 Purkinje细胞（PC）的异质种群表达了小鼠中FOXP1、2和4的不同组合胚胎小脑。通过小脑特异性敲除实验，我们表明了FOXP1或 FOXP2影响了PC多样化。令人惊讶的是，删除FOXP1和2导致小脑的总损失半球已经在哺乳动物中从头发展，并参与了认知和语言功能。我们的长期目标是确定小脑组装下的分子和细胞机制电路。我们假设FOXP1和FOXP2合作指定了PC组的分子身份对于小脑半球的形成和膨胀至关重要。解决这一假设和为我们的目标做出贡献，我们建议：1）使用单细胞转录组学和灯页卷成像确定FOXP1和FOXP2如何调节小脑的PC分化和形态发生，2）确定突变体和对照小脑中FOXP1和FOXP2的全基因组结合曲线。数据综合分析这些目标产生的将揭示由FOXP1组合功能控制的转录网络和发育中的小脑中的FOXP2。拟议的培训计划由大学Yuanhao James Li博士和大学的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提供PI，Nagham Khouri Farah女士，为成功的独立科学家而成功的职业生涯扎实。培训计划将有助于PI获得经验：1）进行多词的实验和分析，2）负责任地进行研究，3）与其他科学家合作，4）以书面和口头格式介绍数据，5）在遗传学，神经科学和发育生物学领域对科学界的贡献。