MicroRNA-Dependent Regulation of Synaptic and Behavioral Plasticity in Drosophila

果蝇突触和行为可塑性的 MicroRNA 依赖性调节

• 批准号: 9910454
• 负责人: Ronald L Davis
• 金额: $ 94.17万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910454
• 关键词: Address; Alleles; Animal Model; Architecture; Behavior; Behavioral; Behavioral Assay; Bioinformatics; Biological Assay; Brain; Brain region; Cellular Assay; Collaborations; Comparative Study; Complex; Country; Coupled; Data; Detection; Development; Dissection; Drosophila genus; Gene Expression Profile; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Transcription; Genetic Translation; Genomics; Goals; Individual; Insecta; Institutes; Institution; Joints; Knowledge; Locomotion; Logic; Mammals; Maps; Mediating; Memory; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Computations; Molecular Genetics; Movement; Nervous system structure; Neuraxis; Neurobiology; Neuronal Plasticity; Neurons; Output; Pathway interactions; Phenotype; Physiological; Proteins; RNA; Reagent; Regulation; Regulator Genes; Research Personnel; Series; Shapes; Signal Transduction; Sleep; Source; Stimulus; Structure; Synaptic plasticity; System; Technical Expertise; Techniques; Testing; Textiles; Time; Transgenic Organisms; Universities; Untranslated RNA; Validation; Work; analytical tool; behavioral plasticity; cell type; computational platform; design; experimental study; genetic strain; improved; in vivo; innovation; loss of function; mRNA Stability; medical schools; mutant; nervous system development; neural circuit; neurodevelopment; overexpression; programs; protein expression; public health relevance; response; sensor; spatiotemporal; tool; transcriptome

 DESCRIPTION (provided by applicant): Precise temporal and spatial regulation of gene expression is essential to many aspects of nervous system development, function and plasticity. Among several classes of gene regulatory factors, non-coding RNAs have emerged as a rich potential source of regulatory mechanism in the central nervous system. In particular, microRNAs (miRs) provide sequence-specific control over target mRNA translation and stability that can tune the levels of downstream proteins quite precisely thus improving the stability and robustness of molecular networks. However, comprehensive analysis of miR function within the intact nervous system has been very challenging, leaving open key questions such as: How complex is the miR regulatory landscape for neural circuits that mediate essential behaviors? Are these miRs acting mainly during neural development or are they reused to manage ongoing neural circuit activity and adaptation to stimuli? To what extent are miR mechanisms utilized in many parts of the brain, or do they regulate distinct sets of target genes in different cell types and/or developmental stages? In order to address these questions, we have assembled a team of accomplished investigators prepared to work in unison using multiple robust behavioral and cellular assays as part of an integrated program. Our team includes Drs. David Van Vactor (Harvard Medical School), Leslie Griffith (Brandeis University), Ronald Davis (Scripps Institute), and Dennis Wall (Stanford University), who will each assume responsibility for key components of this joint program. We will use Drosophila as a model organism that offers many sophisticated genetic tools complementary to the innovative tools we will develop. Drosophila has proven to be particularly effective for identification and dissection of cellular and molecular mechanisms underlying well conserved behaviors. This model is also accessible to a full range of techniques for determining the detailed cellular and physiological phenotypes of mutants in specific pathways, thus offering a system ideal for mapping out miR functions on a comprehensive scale followed by mechanistic dissection that will effectively leverage a wealth of tools and knowledge. Together, we will (i) build and apply new genetic tools, (ii) apply these tools to identify miRs required in multiple neural circuits, (iii) discover the mechanisms and regulatory strategies for miR function in each context, and then (iv) compare each model to distinguish general and specific strategies and examine their conservation. This will be the first analysis of its kind in the nervous system. Our preliminary findings already identify convergence between different circuits that will prioritize our detailed studies of several miRs: miR-13, miR-92, miR-190 and let-7. Preliminary analysis of miR-92 already points to a series of highly conserved downstream genes implicated in both neural circuit development and synaptic plasticity from insects to mammals, providing a set of specific mechanistic hypotheses that we will test in the three model circuits to define the regulatory logic for each validated target.

 描述（由应用提供）：基因表达的精确临时和空间调节对于神经系统发育，功能和可塑性的许多方面至关重要。在几类基因调节因素中，非编码RNA已成为中枢神经系统中调节机制的丰富潜在来源。特别是，microRNA（miR）提供了对目标mRNA平移和稳定性的序列特异性控制，可以非常精确地调整下游蛋白的水平，从而改善了分子网络的稳定性和鲁棒性。但是，对完整神经系统中MIR功能的全面分析非常挑战，留下了关键问题，例如：介导基本行为的神经元电路的miR调节景观有多复杂？这些miR是主要在神经发育过程中起作用吗？还是重复用于管理正在进行的神经回路活动和适应刺激？ MIR机制在大脑的许多部分中使用了多大程度，还是在不同的细胞类型和/或发育阶段调节不同的靶基因集合？为了解决这些问题，我们组建了一支成立的调查人员团队，准备使用多个稳健的行为和蜂窝测定，作为集成程序的一部分。我们的团队包括Drs。戴维·范·瓦特（David Van Vactor）（哈佛医学院），莱斯利·格里菲斯（Leslie Griffith）（布兰代斯大学），罗纳德·戴维斯（Ronald Davis）（斯克里普斯学院）和丹尼斯·沃尔（Dennis Wall）（斯坦福大学），他们将对该联合计划的关键组成部分负责。我们将使用果蝇作为模型生物体，为我们将开发的创新工具提供许多复杂的遗传工具。事实证明，果蝇对于鉴定和解剖细胞和分子特别有效 构成良好行为的机制。该模型也可以使用特定途径中突变体的详细细胞和物理表型的完整技术访问，从而提供了一种理想的系统，用于在全面的规模上绘制MIR功能，然后进行机械剖析，从而有效利用大量工具和知识。 （i）将共同构建和应用新的遗传工具，（ii）应用这些工具来识别多个中性电路中所需的miR，（iii）在每种情况下发现MIR功能的机制和调节策略，然后（iv）将每个模型比较以区分一般和特定策略并检查其保护并进行保护。这将是神经系统中此类人的第一个分析。我们的初步发现已经确定了不同电路之间的融合，这将优先考虑我们对几种miR的详细研究：miR-13，miR-92，mir-190和let-7。对miR-92的初步分析已经指出了一系列在神经回路发育和从昆虫到哺乳动物的突触可塑性中实现的高度保守的下游基因，提供了一组特定的机械假设，我们将在三个模型电路中测试，以定义每个经过验证的目标的调节逻辑。

项目成果

miRNA: local guardians of presynaptic function in plasticity and disease.

• DOI: 10.1080/15476286.2020.1871214
• 发表时间: 2021-07
• 期刊: RNA biology
• 影响因子: 4.1
• 作者: Woods BJ;Van Vactor D
• 通讯作者: Van Vactor D