The Role of NMD in Cortical Neural Progenitor Cells
NMD 在皮质神经祖细胞中的作用
基本信息
- 批准号:10356466
- 负责人:
- 金额:$ 52.01万
- 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:2021-12-01 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAffectBehaviorBiochemicalBiologyBrainCell CycleCell Cycle ProgressionCell Cycle RegulationCell LineageCellsCharacteristicsCollaborationsComputational BiologyCortical MalformationDataDefectDevelopmentDiseaseEnsureEquilibriumEtiologyGenesGeneticGenetic TranscriptionIn VitroKnock-outKnockout MiceKnowledgeLeadLengthLightLinkMacrocephalyMeasuresMediatingMessenger RNAMethodsMicrocephalyMitoticMolecularMothersMutationNeocortexNeurobiologyNeurodevelopmental DisorderNeurogliaNeuronsNeurosciencesNonsense CodonOutputPathogenicityPathway interactionsPhenotypePositioning AttributePost-Transcriptional RegulationProcessRNARNA DecayRNA DegradationRNA ProcessingRNA chemical synthesisRadialRecording of previous eventsRegulationRegulatory PathwayReportingResearchRoleTP53 geneTestingTimeTranscriptTranscriptional Regulationbasecell behaviorcell determinationcell typeconditional knockoutdaughter celldevelopmental neurobiologyin vivoinsightmRNA DecaymRNA Stabilitymouse geneticsnerve stem cellnestin proteinneurodevelopmentneurogenesisneuroregulationnovelprogenitorrelating to nervous systemspatiotemporalstemstem cell differentiationstem cellstooltranscription factortranscriptomics
项目摘要
PROJECT SUMMARY
Mutations in key factors of nonsense-mediated mRNA decay (NMD), including Upf2, Upf3a, Upf3b, and Smg6,
are enriched in various neurodevelopmental diseases. In additional to ensuring transcript quality by degrading
aberrant transcripts with a premature stop codon, NMD modulates stability of selective mRNAs to fine-tune
transcript abundance. Whether and how NMD influences brain development remains elusive. Our long-term
objective is to understand the functional role of NMD regulation for the complicated and dynamic process of
neurogenesis and how its mis-regulation leads to neurodevelopmental disorders. We determine the
requirement of NMD for neural development through selective genetic ablation of Upf2 and in vivo
manipulation of other NMD factors. Our preliminary data show that deletion of UPF2 in neural stem and
progenitors results in microcephaly. UPF2 loss specifically affects the cell cycle and lineage progression of
radial glia cells (RGCs), the major neural progenitor cells in the developing neocortex. We will combine cutting
edge molecular cellular ribogenomics approaches, mouse genetics, and developmental neurobiology to dissect
the mechanisms of NMD regulating neurogenesis. We propose three independent and interrelated aims to
investigate possible variables underlying the microcephaly phenotype. In Aim 1, we will determine the cell
cycle behaviors of RGCs in NMD knockout mice qualitatively and quantitatively and unveil the underlying
regulatory mechanisms. In Aim 2, we will determine the lineage progression of RGCs and the resulting
neuronal outputs per time unit in NMD knockout mice. By characterizing these molecular cellular defects, we
also aim to provide mechanistic insights to transcriptomic regulation of RGC’s lineage transitions. NMD may
regulate cell fates either independent of cell cycle controls or as the consequence of affecting the cell cycle. In
Aim 3, we will test these two hypotheses and leverage our results to reexamine the relationship between cell
cycle and cell fate. Successful completion of these studies will provide fundamental insights into how selective
mRNA stability underlies the highly regulated cortical neurogenesis process in the mammalian brain. The
proposed studies will also shed light on some fundamental questions about the control of cell cycle, cell fate,
and their relationship during neural development.
项目总结
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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{{ truncateString('Sika Zheng', 18)}}的其他基金
The Role of NMD in Cortical Neural Progenitor Cells
NMD 在皮质神经祖细胞中的作用
- 批准号:
10572698 - 财政年份:2022
- 资助金额:
$ 52.01万 - 项目类别:
The Role of NMD in Cortical Neural Progenitor Cells
NMD 在皮质神经祖细胞中的作用
- 批准号:
10755022 - 财政年份:2021
- 资助金额:
$ 52.01万 - 项目类别:
The Role of NMD in Cortical Neural Progenitor Cells
NMD 在皮质神经祖细胞中的作用
- 批准号:
10532374 - 财政年份:2021
- 资助金额:
$ 52.01万 - 项目类别:
The regulation and function of neuron-specific alternative splicing
神经元特异性选择性剪接的调控和功能
- 批准号:
10063921 - 财政年份:2017
- 资助金额:
$ 52.01万 - 项目类别:
The Regulation and Function of Neuron-Specific Alternative Splicing
神经元特异性选择性剪接的调控和功能
- 批准号:
10318594 - 财政年份:2017
- 资助金额:
$ 52.01万 - 项目类别:
Alternative splicing and nonsense-mediated mRNA decay in neural development
神经发育中的选择性剪接和无义介导的 mRNA 衰减
- 批准号:
8834110 - 财政年份:2014
- 资助金额:
$ 52.01万 - 项目类别:
Alternative splicing and nonsense-mediated mRNA decay in neural development
神经发育中的选择性剪接和无义介导的 mRNA 衰减
- 批准号:
9069107 - 财政年份:2014
- 资助金额:
$ 52.01万 - 项目类别:
Alternative splicing and nonsense-mediated mRNA decay in neural development
神经发育中的选择性剪接和无义介导的 mRNA 衰减
- 批准号:
8878168 - 财政年份:2014
- 资助金额:
$ 52.01万 - 项目类别:
Alternative splicing and nonsense-mediated mRNA decay in neural development
神经发育中的选择性剪接和无义介导的 mRNA 衰减
- 批准号:
8507514 - 财政年份:2013
- 资助金额:
$ 52.01万 - 项目类别:
Alternative splicing and nonsense-mediated mRNA decay in neural development
神经发育中的选择性剪接和无义介导的 mRNA 衰减
- 批准号:
8641419 - 财政年份:2013
- 资助金额:
$ 52.01万 - 项目类别:
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