Regulation of Synapse Morphogenesis in Drosophila

果蝇突触形态发生的调控

基本信息

批准号：
8442877
负责人：
David L. Van Vactor
金额：
$ 35.06万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
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/8442877
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

项目摘要

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.

描述（由申请人提供）：调节突触形式和功能的分子途径功能障碍会导致许多神经系统疾病，包括癫痫、自闭症和智力低下。我们的目标是探索介导突触发育和形态发生的分子机制。这些基础知识对于我们理解神经系统疾病和未来治疗工具的概念非常重要。使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microRNA（miRNA）miR-200家族的成员，对于突触的正常生长和复杂性至关重要。缺乏 miR-8 的动物在不同的发育阶段表现出 NMJ 缺陷。在幼虫阶段，当 NMJ 在多种刺激和调控途径的控制下急剧扩张时，肌肉细胞中需要 miR-8 来促进突触前末梢的生长。我们的分析表明，miR-8 是细胞基质正常结构所必需的，细胞基质定义了 NMJ 的突触下网状结构 (SSR)，这种结构类似于哺乳动物中 PSD-95 标记的突触后密度。定义下游效应子的多重筛选表明，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。为了更好地定义 miR-8 的下游机制，我们发现肌动蛋白相关蛋白 Enabled (Ena) 的突触后抑制在控制幼虫晚期 NMJ 生长方面发挥着重要作用，这与 Ena 在 SSR 中的定位一致。 Ena 预计是 miR-8 的直接靶标，并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尚不清楚。初步数据还表明，尽管 miR-8 在中枢神经系统 (CNS) 中表达，但相对于其他组织，其活性在神经元中受到某种程度的抑制。此外，遗传上位性表明 miR-8 是通过激活限制突触形态发生的关键突触前通路（Fragile-X 智力迟钝基因，FMR1）诱导的 NMJ 扩展所必需的，这表明上游涉及某种类型的跨突触通讯突触后 miR-8。总之，这些发现揭示了调节突触发育的令人着迷的机制，以及利用强大且定义明确的模型系统来理解 miRNA 对突触形式和功能的控制逻辑的绝佳机会。然而，还需要进行许多额外的研究来确定 miR-8 在 NMJ 上发挥作用所需的发育、细胞和分子机制。