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Role of miRNAs in the development and function of a circuit for vocal learning

miRNA 在声音学习回路的发育和功能中的作用

基本信息

批准号：
9406348
负责人：
XIAOCHING LI
金额：
$ 36.5万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9406348
关键词：
3&apos Untranslated Regions Adolescent Adult Affect Area Behavioral Brain Broca&apos s area Cell Nucleus Cell Proliferation Cerebellum Corpus striatum structure Dendritic Spines Development Embryo Environmental Risk Factor FOXP1 gene FOXP2 gene Finches Gene Expression Genes Genetic Genetic Transcription Genetic study Impairment In Vitro Individual Language Lead Learning Mediating Mental disorders Messenger RNA MicroRNAs Molecular Motor Mutation Neurons Newborn Infant Open Reading Frames Outcome Performance Play Procedures Protein Biosynthesis Regulation Regulator Genes Research Role Site Speech Structure Subfamily lentivirinae Testing Therapeutic Agents Untranslated RNA Ventricular adult neurogenesis autism spectrum disorder base density developmental disease diagnostic biomarker dimer experimental study imaging study in vivo insight knock-down language impairment lateral ventricle learned behavior mRNA Transcript Degradation nerve stem cell nervous system development nervous system disorder neural circuit neurogenesis novel novel diagnostics paralogous gene postnatal public health relevance recruit relating to nervous system therapeutic target transcription factor vocal learning young adult zebra finch

项目摘要

DESCRIPTION (provided by applicant): miRNAs are small non-coding RNA molecules that regulate gene expression by targeting the 3'-untranlated regions (UTRs) of mRNAs leading to mRNA degradation and suppression of protein synthesis. By coordinating and tuning gene expression, miRNAs play important roles in nervous system development and function. Dysregulation of miRNAs may lead to neural developmental disorders and mental illness. Here we propose to study two brain-enriched miRNAs, miR-9 and miR-139-5p, which potentially regulate the FOXP1 and FOXP2 genes. FOXP1 and FOXP2 are paralog transcription factors that function as a dimer and regulate the expression of numerous downstream genes important in neural circuit development. Mutations in the FOXP2 gene cause speech and language impairments, and both FOXP1 and FOXP2 have also been implicated in the Autism Spectrum Disorders (ASDs). An emerging hypothesis suggests that an adequate amount of functional FOXP2 is required for the proper development of the distributed neural circuitry for procedure learning and motor sequencing required for speech and language. However, regulation of the expression of FOXP1 and FOXP2 is not clear. Both the FOXP1 and FOXP2 genes have long 3'-UTRs (~4 kb), twice as long as their respective protein coding regions, suggesting that they are regulated by miRNAs. miR-9 and miR-139-5p are evolutionarily conserved and their targeting sites in the 3'-UTRs of FOXP1 and FOXP2 are also conserved, allowing us to study them in the zebra finch in the context of neural circuit development and vocal learning behavior. In the zebra finch brain, FOXP1 and FOXP2 are expressed in Area X, a nucleus in a cortical-striatal circuit required for vocal learning in juvenile zebra finches. Knockdown of FoxP2 in Area-X impairs vocal learning and reduces dendritic spine density in juvenile finches. Area X is largely composed of spiny neurons and a considerable number of new spiny neurons are generated in the germinal lining of the lateral ventricle adjacent to Area X and being recruited into Area X in young and adult zebra finches. We have shown that both miR-9 and miR-139-5p are expressed in Area X and in the ventricular zone. miR-9 is also known to regulate neural progenitor proliferation and differentiation during embryonic brain development. These collective observations led us to hypothesize that miR-9 and miR-139-5p regulate FOXP1 and FOXP2, and play important roles in regulating postnatal neurogenesis, neuronal dendritic development, and vocal learning behavior. This hypothesis will be tested using a combination of molecular, cellular, and behavioral approaches. First, we will test whether miR-9 and miR-139-5p regulate FoxP1 and FoxP2 in vitro; we will also examine how the expression of miR-139-5p and FoxP1 is regulated in the zebra finch brain during vocal development and in adults (we already studied miR-9 and FoxP2). Then we will use lentiviruses to manipulate the expression of miR-9 and miR-139-5p in Area X and test the effects on vocal learning and performance. We will also study the roles of miR-9 and miR-139-5p in regulating neurogenesis in postnatal and adult Area X, and study the roles of miR-9 and miR-139-5p in regulating dendritic structures in spiny neurons in Area X. This research promises to establish novel post-transcriptional regulatory relationships between miR-9/miR- 139-5p and FOXP1/FOXP2, and to delineate the roles of miR-9 and miR-139-5p in regulating neurogenesis and dendritic development in a neural circuit important for vocal learning behavior. As the striatum is at the center of many mental illness and neurological disorders, these results may open new opportunities to study how genetic and environmental factors contribute to these conditions via miRNA-mediated gene regulatory networks. With further research, these miRNAs may be developed into diagnostic markers or therapeutic agents.