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Dynamic control of cortical development and disease by mRNA stability

通过 mRNA 稳定性动态控制皮质发育和疾病

基本信息

批准号：
10510361
负责人：
Debra Silver
金额：
$ 44.28万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10510361
关键词：
Address Atlases Behavior Bioinformatics Biological Assay Brain Cells Cerebral cortex Complement Complex Data Data Set Development Diagnostic Disease Embryo Ensure Equilibrium Foundations Future Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Glutamates Goals Hour Human Human Development Impairment Label Light Measurement Measures Messenger RNA Metabolism Methods Microcephaly Molecular Mus Mutate Mutation Nature Nervous system structure Neurodevelopmental Disorder Neurons Pathogenicity Pathology Physiologic pulse Post-Transcriptional Regulation Proteins RNA RNA Decay RNA Degradation RNA Stability RNA-Binding Proteins Regulation Research Role Scaffolding Protein Shapes Surveys Testing Therapeutic Time Transcript Variant autism spectrum disorder base cell type experimental study human embryonic stem cell human model in vivo insight knock-down mRNA Decay mRNA Stability mind control mouse development mouse model mutant nerve stem cell nervous system disorder neural circuit neurogenesis neuropsychiatric disorder nucleotide analog progenitor protein complex relating to nervous system single cell analysis transcriptome transcriptomics

项目摘要

Abstract Development of the cerebral cortex requires precise regulatory control to ensure genes are expressed in the correct cell types and at the proper developmental stages. Analyses of gene expression across cell types and development, have revealed extensive diversity in cellular transcriptomes. However, transcriptomic datasets only provide a static snapshot of gene expression. Transcript expression is influenced by a balance between rates of transcription and RNA degradation, yet the role of the latter in cortical development is poorly understood. The overall goal of this proposal is uncover how mRNA stability contributes to the dynamic nature of cellular transcriptomes across cortical development. First, we will elucidate, for the first time, the temporal landscape of mRNA stability during cortical development. We will use state-of-the-art SLAM-seq approaches to quantify mRNA stability across neural differentiation stages in both mouse and human models. These data will be interrogated to inform both cis and trans control of RNA degradation and to prioritize disease loci influenced by stability. Second, we will investigate requirements for components of the CCR4-NOT complex, a central regulator of RNA stability, in cortical development. Our preliminary data demonstrate the CNOT3 component is essential for cortical development. Thus, we will use knockdown approaches and rescue experiments to measure the extent to which CNOT3 controls cortical development as part of the CCR4-NOT complex. Further, as components of this complex are mutated in autism, we will investigate how these mutations impair cortical development. Upon completion, our studies will establish the first comprehensive repertoire of mRNAs that are dynamically regulated at the level of stability in mouse and human development. By investigating genetic requirements of RNA stability factors for corticogenesis, we will establish new paradigms for how cell fate is regulated in the nervous system and relevant for disease. Together, this will open up new research directions into the basis of molecular control of brain development and disease.

摘要