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:10676978
- 负责人:
- 金额:$ 4.42万
- 依托单位:
- 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:
- 关键词:AddressAdultAffectAffinityAnimal ModelAtaxiaAttentionAutomobile DrivingBilateralBindingBiochemicalBiological AssayCell Differentiation processCellsCellular MorphologyCerebellar CortexCerebellar DiseasesCerebellar vermis structureCerebellumChromatinCognition DisordersCognitiveCollaborationsCommunitiesCompetitive BindingConnecticutDNA BindingDNA SequenceDataData AnalysesData SetDevelopmentDevelopmental BiologyEmbryoEnhancersEquilibriumEventFOXP1 geneFOXP2 geneFoundationsGene ExpressionGene Expression ProfileGenerationsGenesGeneticGenetic TranscriptionGenomic SegmentGoalsHealthHeterogeneityHomoImageImpairmentIndividualKnock-outKnockout MiceLanguageLearningLigandsLightLinkMammalsMental RetardationMolecularMorphogenesisMorphologyMovementMusMutationNeurodevelopmental DisorderNeuronsNeurosciencesOralOutcomePerceptionPopulationPopulation HeterogeneityPromoter RegionsProsencephalonPurkinje CellsRoleScienceScientistSensorySignal PathwaySignal TransductionSolidSpecific qualifier valueSpeechTestingTrainingUniversitiesWritingautism spectrum disordercareercell motilitycognitive functioncombinatorialdifferential expressionexperienceexperimental studygene networkgenome-widein vivoinsightinventionlanguage impairmentmultiple omicsmutantpostnatalpreservationpreventreceptorresponsible research conductsingle-cell RNA sequencingtranscription factortranscriptometranscriptomics
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。在动物模型中的功能研究表明
FOXP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
对它们的作用机制缺乏了解。我们最近发现,在分子水平上
小鼠体内不同群体的浦肯野细胞表达Foxp1、2和4的不同组合
胚胎小脑。通过小脑特异的基因敲除实验,我们发现Foxp1或Foxp1基因的缺失
Foxp2影响了PC的多样化。引人注目的是,同时删除Foxp1和Foxp2会导致小脑完全丧失
大脑半球,它在哺乳动物中从头进化,并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协同指定PC基团的分子同一性
对小脑半球的形成和扩张至关重要。为了解决这一假设,并
为了实现我们的目标,我们建议:1)使用单细胞转录和光片体积成像技术
确定Foxp1和Foxp2如何调节小脑PC的分化和形态发生;2)确定
Foxp1和Foxp2在突变和对照小脑中的全基因组结合图谱。数据的综合分析
从这些目的产生的将解开由Foxp1的组合功能控制的转录网络
和发育中的小脑中的Foxp2。
拟议的培训计划由加州大学的李元浩博士和贾斯汀·科特尼博士赞助
康涅狄格州健康中心。该培训计划的总体目标是为国际和平协会、纳格哈姆·库里·法拉赫女士、
拥有作为一名独立科学家的成功职业生涯的坚实基础。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)以书面和口头形式展示数据,5)做出有意义的
在遗传学、神经科学和发育生物学领域对科学界的贡献。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Nagham Khouri Farah其他文献
Nagham Khouri Farah的其他文献
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{{ truncateString('Nagham Khouri Farah', 18)}}的其他基金
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:
10459286 - 财政年份:2021
- 资助金额:
$ 4.42万 - 项目类别:
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:
10313573 - 财政年份:2021
- 资助金额:
$ 4.42万 - 项目类别:
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