Regulation of Synapse Morphogenesis in Drosophila

果蝇突触形态发生的调控

• 批准号: 8248274
• 负责人: David L. Van Vactor
• 金额: $ 36.34万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248274
• 关键词: Accounting; Actins; Animals; Architecture; Autistic Disorder; Biological Models; Biology; Brain; Cell Adhesion Molecules; Cells; Communication; Conceptions; Data; Defect; Development; Disease; Dissection; Drosophila genus; Embryo; Epilepsy; FMR1 Gene; Family; Fragile X Syndrome; Functional disorder; Future; Gene Targeting; Genes; Genetic Epistasis; Genetic Models; Goals; Growth; Impaired cognition; Intercellular Junctions; Knowledge; Logic; Maintenance; Mammals; Mediating; Mental Retardation; MicroRNAs; Modeling; Molecular; Molecular Analysis; Morphogenesis; Muscle; Muscle Cells; Neuraxis; Neuromuscular Junction; Neurons; Organism; Orthologous Gene; Pathway interactions; Phenocopy; Phenotype; Physiology; Play; Presynaptic Terminals; Proteins; Proteomics; Regulation; Regulatory Pathway; Relative (related person); Repression; Reticulum; Role; Signal Transduction; Staging; Stimulus; Structure; Surveys; Synapses; Testing; Therapeutic; Tissues; brain malformation; cell motility; cytomatrix; density; fascinate; gain of function; in vivo; insight; loss of function; member; nervous system disorder; neuroglian; postsynaptic; presynaptic; public health relevance; relating to nervous system; synaptic function; synaptogenesis; tool

DESCRIPTION (provided by applicant): Dysfunction in the molecular pathways that regulate synapse form and function leads to a number of neurological disorders, including epilepsy, autism and mental retardation. Our goal is to explore the molecular machinery that mediates synapse development and morphogenesis. This fundamental knowledge will be important for our understanding of neurological disease and for the conception of future therapeutic tools. Using the Drosophila neuromuscular junction (NMJ) as a genetic model system, we have discovered that miR- 8, a member of the highly conserved miR-200 family of microRNAs (miRNAs), is essential for the normal growth and complexity of the synapse. Animals lacking miR-8 display NMJ defects at different stages of development. During larval stages, when NMJs dramatically expand under control of multiple stimuli and regulatory pathways, miR-8 is required in muscle cells to promote the growth of presynaptic terminals. Our analysis suggests that miR-8 is required for the normal architecture of the cytomatrix which defines subsynaptic reticulum (SSR) of the NMJ, a structure analogous to the postsynaptic density marked by PSD-95 in mammals. Multiple screens to define downstream effectors suggest that miR-8 regulates the expression of several target genes implicated in synaptogenesis and cytoskeletal biology. To better define the mechanisms downstream of miR-8, we have shown that postsynaptic repression of the actin-associated protein Enabled (Ena) plays an important role in controlling NMJ growth in late larval stages, consistent with the localization of Ena to the SSR. Ena is predicted to be a direct target of miR-8, and controls aspects of cytoskeletal structure and dynamics during cell movement and cell junction formation, but its role(s) at the synapse are not understood. Preliminary data also indicate that although miR-8 is expressed in the central nervous system (CNS), its activity is somehow suppressed in neurons relative to other tissues. Moreover, genetic epistasis reveals that miR-8 is required for NMJ expansion induced by activation of a key presynaptic pathway that limits synapse morphogenesis (the Fragile-X Mental Retardation gene, FMR1), suggesting that some type of trans- synaptic communication is involved upstream of postsynaptic miR-8. Together, these findings reveal a fascinating mechanism that regulates synapse development, and a wonderful opportunity to exploit a powerful and well-defined model system to understand the logic of miRNA control over synapse form and function. However, many additional studies will be required to define the developmental, cellular and molecular mechanisms required for miR-8 to exert its effects at the NMJ. PUBLIC HEALTH RELEVANCE: Recent insights reveal that microRNAs provide essential regulatory mechanisms during synapse development. Dysfunction in the molecules and pathways that control synaptic morphogenesis leads to neurological disorders such as mental retardation and autism, however, our understanding of the regulatory mechanisms upstream is limited. We will determine the strategy by which Drosophila miR-8 promotes synapse formation as a model to better define the logic of pathways upstream and downstream of synaptic microRNAs.

描述(由申请人提供)：调节突触形式和功能的分子通路功能障碍会导致许多神经疾病，包括癫痫、自闭症和智力低下。我们的目标是探索调节突触发育和形态发生的分子机制。这一基础知识对于我们理解神经系统疾病和构思未来的治疗工具将是重要的。利用果蝇神经肌肉接头(NMJ)作为遗传模型系统，我们发现miR-8是高度保守的miR-200 microRNAs(MiRNAs)家族成员之一，对于突触的正常生长和复杂性是必不可少的。缺乏miR-8的动物在发育的不同阶段表现出NMJ缺陷。在幼虫期，当NMJ在多种刺激和调节途径的控制下急剧扩张时，肌肉细胞中需要miR-8来促进突触前终末的生长。我们的分析表明，miR-8是定义NMJ突触下网(SSR)的细胞矩阵正常结构所必需的，这种结构类似于哺乳动物中PSD-95标记的突触后密度。定义下游效应器的多个筛选表明，miR-8调节与突触发生和细胞骨架生物学有关的几个靶基因的表达。为了更好地确定miR-8下游的机制，我们已经证明，突触后抑制肌动蛋白相关蛋白使能(Ena)在控制幼虫晚期NMJ生长方面发挥着重要作用，这与EnA在SSR上的定位一致。EnA被预测为miR-8的直接靶标，在细胞运动和细胞连接形成过程中控制细胞骨架结构和动力学的各个方面，但其在突触中的作用(S)尚不清楚。初步数据还表明，虽然miR-8在中枢神经系统(CNS)中表达，但其活性在神经元中相对于其他组织受到某种程度的抑制。此外，遗传上位论揭示，miR-8是通过激活限制突触形态发生的关键突触前通路(脆性X智力低下基因，FMR1)而诱导的NMJ扩张所必需的，这表明突触后miR-8上游参与了某种类型的跨突触通信。综上所述，这些发现揭示了一种令人着迷的调节突触发育的机制，也是利用一个强大且定义明确的模型系统来理解miRNA控制突触形式和功能的逻辑的绝佳机会。然而，还需要更多的研究来确定miR-8在NMJ发挥作用所需的发育、细胞和分子机制。 与公共健康相关：最近的洞察力表明，microRNAs在突触发育过程中提供了必要的调节机制。控制突触形态发生的分子和途径的功能障碍会导致智力低下和自闭症等神经疾病，然而，我们对上游调控机制的了解有限。我们将确定果蝇miR-8促进突触形成的策略作为模型，以更好地定义突触microRNAs上游和下游通路的逻辑。