Cytoplasmic Functions of Rbfox1, a Candidate Autism Gene

自闭症候选基因 Rbfox1 的细胞质功能

基本信息

批准号：
8695492
负责人：
Kelsey C Martin
金额：
$ 19.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8695492
关键词：
3&apos Untranslated Regions Affect Autistic Disorder Binding Binding Sites Biological Biological Assay Brain Canis familiaris Cell Nucleus Cells Chickens Computer Simulation Cytoplasm Cytosol Data Dendrites Fragile X Mental Retardation Protein Functional disorder Gene Expression Genes Genetic Translation Goals Hippocampus (Brain)Human Human Genetics Immunoblotting Immunoprecipitation Individual Luciferases Mediating Messenger RNA MicroRNAs Molecular Target Mus Mutation Neurodevelopmental Disorder Neurons Nuclear Nucleotides Protein Splicing Proteins RNA RNA Processing RNA Sequences RNA Splicing RNA-Binding Proteins Rattus Regulation Reporter Research Resolution Reverse Transcriptase Polymerase Chain Reaction Role Small Interfering RNA Stretching Susceptibility Gene Synapses Transcript Translational Regulation Translational Repression Translations Viral Vector autism spectrum disorder candidate identification crosslink insight mRNA Stability neural circuit public health relevance research study trafficking

项目摘要

DESCRIPTION (provided by applicant): Abnormalities in RNA processing and translation within neurons likely contribute to Autism Spectrum Disorders (ASD). For example, mutations in Fragile X Mental Retardation protein, an RNA binding protein involved in RNA trafficking and translational regulation at the synapse, represent the most common single gene cause of ASD. More recently, human genetic studies identified the RNA binding protein Rbfox1 (also known as A2BP1) as another candidate autism gene. Rbfox1 binds a well-defined RNA sequence, (U)GCAUG, and functions in the nucleus as a regulator of RNA splicing. Rbfox1 itself is alternatively spliced into nuclear and cytoplasmic forms. We show that cytoplasmic Rbfox1 localizes to dendrites and synapses in mouse hippocampal neurons. Many neuronal RNAs contain conserved (U)GCAUG stretches in their 3' untranslated regions (3'UTRs), and our data indicate that cytoplasmic Rbfox1 regulates the stability and/or translation of these mRNAs. In addition, our experiments suggest that Rbfox1 regulates translation by interfering with microRNA (miRNA)-mediated translational repression of some target mRNAs. Many of the mRNA targets of cytoplasmic Rbfox1 have been identified as targets of Rbfox1 in a module of genes that are down regulated in brains of autistic subjects. We propose that dysregulation of mRNA stability and translation in neurons is an important component of the pathophysiology of ASD. Our proposal is aimed at 1) identifying the cytoplasmically localized mRNA targets of Rbfox1 and at 2) determining the mechanisms whereby Rbfox1 regulates their stability and/or translation. The results of our proposed studies may reveal fundamental cell biological mechanisms and specific molecular targets that underlie neural circuit dysfunction in neurodevelopmental disorders, including Autism Spectrum Disorders.

描述（由申请人提供）：神经元内RNA处理和翻译的异常可能导致自闭症谱系障碍（ASD）。例如，脆弱的X智力低下蛋白（一种参与RNA运输的RNA结合蛋白和突触调节的RNA结合蛋白）代表了ASD的最常见的单个基因原因。最近，人类遗传研究将RNA结合蛋白RBFOX1（也称为A2BP1）鉴定为另一个候选自闭症基因。 RBFOX1结合了定义明确的RNA序列（U）GCAUG，并在细胞核中作为RNA剪接的调节剂的功能。 RBFOX1本身被剪接为核和细胞质形式。我们表明，细胞质RBFOX1定位于小鼠海马神经元中的树突和突触。许多神经元RNA在其3'未翻译区域（3'UTRS）中包含保守的（U）GCAUG伸展，我们的数据表明细胞质RBFOX1调节这些mRNA的稳定性和/或翻译。此外，我们的实验表明，RBFOX1通过干扰microRNA（miRNA）介导的某些靶mRNA的翻译抑制来调节翻译。在自闭症受试者大脑中调节的基因模块中，许多细胞质RBFOX1的mRNA靶标已被鉴定为RBFOX1的靶标。我们认为，神经元中mRNA稳定性和翻译的失调是ASD病理生理学的重要组成部分。我们的建议针对1）确定RBFOX1的细胞质局部局部mRNA靶标，并在2）确定RBFOX1调节其稳定性和/或翻译的机制。我们提出的研究的结果可能揭示了基本的细胞生物学机制和特定的分子靶标，这些机制是神经发育障碍（包括自闭症谱系障碍）中神经回路功能障碍的基础。