Cytoplasmic Functions of Rbfox1, a Candidate Autism Gene

自闭症候选基因 Rbfox1 的细胞质功能

• 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
• 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' 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

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 加工和翻译的异常可能导致自闭症谱系障碍 (ASD)。例如，脆性 X 型智力迟钝蛋白（一种参与 RNA 运输和突触翻译调节的 RNA 结合蛋白）的突变代表了自闭症谱系障碍 (ASD) 最常见的单基因原因。最近，人类遗传学研究发现 RNA 结合蛋白 Rbfox1（也称为 A2BP1）是另一个候选自闭症基因。 Rbfox1 结合明确的 RNA 序列 (U)GCAUG，并在细胞核中作为 RNA 剪接的调节器发挥作用。 Rbfox1 本身选择性地剪接成细胞核和细胞质形式。我们发现细胞质 Rbfox1 定位于小鼠海马神经元的树突和突触。许多神经元 RNA 在其 3' 非翻译区 (3'UTR) 中含有保守的 (U)GCAUG 延伸，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) 介导的一些靶 mRNA 的翻译抑制来调节翻译。细胞质 Rbfox1 的许多 mRNA 靶标已被确定为 Rbfox1 基因模块中的靶标，这些基因模块在自闭症受试者的大脑中下调。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。我们的建议旨在 1) 识别 Rbfox1 的细胞质定位 mRNA 靶点，2) 确定 Rbfox1 调节其稳定性和/或翻译的机制。我们提出的研究结果可能揭示神经发育障碍（包括自闭症谱系障碍）中神经回路功能障碍的基本细胞生物学机制和特定分子靶标。