Translational control of sensory identity

感官识别的翻译控制

基本信息

批准号：
9894784
负责人：
Rachel Duffie
金额：
$ 16.2万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894784
关键词：
Affect Alleles Animals Axon Binding Biological Assay Brain Cell Maturation Cells Chemicals Cilia Conflict (Psychology)Cues Data Deaminase Detection Development Environment Epithelial Epithelium Epitopes Fluorescence-Activated Cell Sorting Gene Expression Gene Expression Profile Gene Expression Regulation Gene Proteins Generations Genes Genetic Genetic Transcription Heart Human Immunoprecipitation Individual Kinetics Labyrinth Life Light Link Maps Messenger RNA Neurodevelopmental Disorder Neuronal Differentiation Neurons Nose Odors Olfactory Epithelium Olfactory Pathways Patients Pattern Perception Play Post-Transcriptional Regulation Proteins RNA RNA Binding RNA Interference RNA Recognition Motif RNA-Binding Proteins Receptor Gene Regulation Regulator Genes Repression Role Secure Sensory Sensory Disorders Supporting Cell System Testing Therapeutic Time Transcript Transgenic Organisms Translating Translations Work cell regeneration conditional knockout crosslink experimental study gain of function gene repression genome-wide in vitro Assay loss of function mutant nervous system development novel olfactory bulb olfactory receptor olfactory sensory neurons overexpression prevent progenitor promoter receptive field receptor sensory system single-cell RNA sequencing ubiquitin-protein ligase

项目摘要

Abstract Sensory epithelia provide the link between the surrounding environment and its neuronal representation in the brain. The main olfactory epithelium (MOE) permits detection of volatile chemicals by selective activation of olfactory sensory neurons (OSNs), whose identity is defined by singular expression of an olfactory receptor gene (OR). Singular OR choice enables OSN maturation, defines the receptive field of the cell, and determines its axonal targeting to glomeruli in the olfactory bulb. Patterns of glomeruli activity are believed to represent the functional topographic map of odorant cues in the environment. Thus, expression of a singular OR is required for proper neuronal identity, axonal wiring, and odorant perception. Surprisingly, recent single cell RNA-Seq data suggest that individual immature neurons may express multiple OR mRNA transcripts, which is in direct conflict with the longstanding “one-receptor one-neuron” hypothesis. Our work has identified the RNA binding protein Mex3a in immature OSNs as a post-transcriptional regulator that may repress OR transcripts from being translated before one OR is selected for singular expression. Genetic gain of function experiments assign Mex3a as a guardian of the immature neuron state, potentially by binding OR mRNAs directly to prevent their translation, or by targeting an entire class of transcripts such as cilia directed proteins. We propose to identify the direct RNA targets of Mex3a in the MOE, and determine how neuronal differentiation and OR choice are affected in genetic loss of function animals. These studies are poised to unveil a novel post-transcriptional mechanism for regulation of stochastic choice, and will also uncover gene regulatory networks responsible for maintaining progenitor states in sensory cells.

抽象的感觉上皮提供了周围环境与其神经元表示之间的联系脑。主嗅觉上皮（MOE）允许通过选择性激活检测挥发性化学物质嗅觉感觉神经元（OSN），其身份是通过嗅觉接收器的单数表达来定义的基因（OR）。单数或选择使OSN成熟，定义了单元的相关场并确定它的轴突靶向嗅球中的肾小球。人们认为肾小球活动的模式代表环境中气形提示的功能地形图。那是单数或需要的表达令人惊讶的是，最近的单细胞RNA-seq 数据表明，个体未成熟的神经元可能表达多个或mRNA转录本，这是直接的与长期存在的“一受体单神经元”假设发生冲突。我们的工作已将未成熟OSN中的RNA结合蛋白MEX3A视为转录后调节剂这可能会抑制或转录本在一个之前翻译或被选中以进行单数表达。功能实验的遗传增益将MEX3A分配为未成熟神经元状态的监护人，可能是由直接绑定或mRNA以防止其翻译，或针对整个成绩单（例如纤毛指导蛋白质。我们建议确定MEE中MEX3A的直接RNA靶标，并确定如何神经元分化和或选择在功能动物的遗传丧失中受到影响。这些研究是准备揭示一种新型的转录后机制，以调节随机选择的调节，也将发现负责维持感觉细胞中祖细胞状态的基因调节网络。