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.