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The role of the mRNA decay factor CNOT3 in cortical development

mRNA衰减因子CNOT3在皮质发育中的作用

基本信息

批准号：
10388793
负责人：
Lucas Serdar
金额：
$ 6.76万
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：
2022-02-10 至 2025-02-09
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10388793
关键词：
Address Affect Apoptosis Area Brain Cell Cycle Cell Cycle Regulation Cell physiology Cells Cerebral cortex Data Data Set Defect Development Developmental Delay Disorders Disease Electroporation Embryo Equilibrium Event Excision Exhibits Frequencies Gene Expression Gene Expression Regulation Genes Genetic Transcription Image Impairment In Vitro Inherited Intellectual functioning disability Knockout Mice Knowledge Label Lead Learning Disabilities Light Link Maintenance Measures Mediating Messenger RNA Metabolic Microcephaly Missense Mutation Monitor Mus Mutate Neurons Nonsense Mutation Patients Poly(A) Tail Population Post-Transcriptional Regulation Process Proliferating Proteins RNA RNA Decay RNA Stability RNA analysis Radial Regulation Role Technology Testing Thick Transcript Transcriptional Regulation Work autism spectrum disorder cell type cognitive function cohort conditional knockout density excitatory neuron experimental study imaging approach in utero in vivo insight loss of function mRNA Decay mRNA Stability mRNA Transcript Degradation mouse model mutant nerve stem cell neurogenesis novel progenitor relating to nervous system self-renewal stem cell fate stem cells transcriptome sequencing

项目摘要

ABSTRACT Proper spatial and temporal control of gene expression during development of the cerebral cortex is critical for the maintenance of neural progenitors and for neural differentiation. While transcriptional regulation has long been recognized as critical to the control of gene expression during cortical development, the contribution of RNA decay is less well understood. Despite this, mis-regulation regulation of gene expression at the post-transcriptional level is emerging as a major cause of neurodevelopmental diseases, including intellectual disability and autism. CNOT3, a regulator of mRNA stability, has recently been found to be mutated in a cohort of patients suffering from intellectual disability and autism. Additional studies have shown that CNOT3 regulates the stability of transcripts encoding proteins involved in cell cycle regulation and stem cell fate. Despite the links between Cnot3, mRNA degradation, neurodevelopmental disease, how Cnot3 contributes to brain development, and its key targets in this process, are unknown. I will address this knowledge gap using a Cre-lox conditional knockout mouse model to ablate Cnot3 expression in neural progenitors. Preliminary data indicates that at embryonic day (E)14.5 (approximately mid-neurogenesis), cKO mice exhibit microcephaly, apoptosis, and a reduction in the number of actively proliferating cells. In this proposal, I will build upon these observations and test the overall hypothesis that that CNOT3-mediated regulation of mRNA stability is required for proper cortical development. Aim 1 investigates the impact of Cnot3 disruption across corticogenesis, and uses live imaging approaches to monitor the requirements for CNOT3 in progenitor fate decisions. Aim 2 uses state-of-the-art technology to globally monitor mRNA stability in neural progenitors and assess the consequences of Cnot3 deletion on mRNA stability. These approaches will reveal previously uncharacterized role for CNOT3 in cortical development, while providing an unprecedented view of RNA stability during cortical development, and how its mis-regulation contributes to disease.

摘要