Mechanisms of actin regulation in synaptogenesis versus axon guidance

突触发生与轴突引导中肌动蛋白的调节机制

• 批准号: 8524257
• 负责人: Claire Elissa Richardson
• 金额: $ 4.92万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8524257
• 关键词: Actins; Affect; Autistic Disorder; Axon; Biological Process; Caenorhabditis elegans; Cells; Cues; Cytoskeleton; Development; F-Actin; Genes; Genetic; Genetic Models; Genetic Screening; Growth Cones; Link; Mammals; Mediating; Membrane; Microfilaments; Morphology; Nervous system structure; Neurons; Parkinson Disease; Pathway interactions; Pattern; Play; Process; Proteins; Receptor Signaling; Regulation; Relative (related person); Research; Role; Semaphorins; Signal Pathway; Signal Transduction; Specific qualifier value; Stereotyping; Structure; Synapses; Testing; Vesicle; Williams Syndrome; axon guidance; design; effective therapy; gene function; genetic analysis; in vivo; mutant; nervous system disorder; neural circuit; neuron development; novel; presynaptic; programs; public health relevance; receptor; receptor function; response; scaffold; synaptogenesis

DESCRIPTION (provided by applicant): Axon guidance and synaptogenesis represent distinct biological processes in the development of a neuron, yet they are mediated by an overlapping set of extrinsic cues, including netrin, wnt, and semaphorin. In axon guidance, these cues modulate the formation of actin filaments (F- actin) into the filopodial extensions of the growth cone, whereas in synaptogenesis, they direct F-actin assembly at nascent presynaptic regions to scaffold the recruitment of the presynaptic assembly program. To ascertain how the same extrinsic cues instruct dissimilar actin dynamics when specifying axon guidance versus synaptogenesis, we will examine the mechanisms of actin regulation during these two processes in Caenorhabditis elegans. As C. elegans is translucent, its stereotyped axon morphology and synapse patterning are easily observed using cell- and synapse-specific fluorescent markers. Furthermore, the ease of conducting forward genetic screens, combined with the wealth of available characterized mutants, makes C. elegans a powerful genetic model for the study of neuronal development. We will first investigate the relative contribution of known actin regulators to axon guidance and synaptogenesis in a specific neuron. We hypothesize that subsets of actin regulators have an exclusive role in either axon guidance or synaptogenesis, and that the differential regulation and function of these actin regulators underlies the distinct actin dynamics involved in these two processes. In parallel, we will use a forward genetic approach to identify novel genes which link synapse-patterning cues to presynaptic F-actin assembly. Finally, by examining genetic interactions between actin regulators and the multiple extrinsic cues which mediate axon guidance and synaptogenesis in a single cell, we will uncover how these cues converge to modulate actin dynamics. Aberrant actin regulation in neurons has been linked to a number of neurological disorders, including Parkinson's disease and autism. A more complete understanding of the mechanisms of actin regulation in neurons is an important step in designing effective therapies for these conditions.

描述（由申请人提供）：轴突引导和突触发生代表神经元发育中的不同生物学过程，但它们由一组重叠的外部线索介导，包括netrin、wnt和semaphorin。在轴突引导中，这些线索调节肌动蛋白丝（F-肌动蛋白）形成为生长锥的丝状伪足延伸，而在突触发生中，它们指导新生突触前区域的F-肌动蛋白组装以支撑突触前组装程序的募集。为了确定如何相同的外在线索指示不同的肌动蛋白动力学时，指定轴突的指导与突触，我们将研究肌动蛋白调节的机制，在这两个过程中的秀丽隐杆线虫。作为C. elegans是半透明的，其定型的轴突形态和突触图案很容易使用细胞和突触特异性荧光标记物观察。此外，易于进行正向遗传筛选，结合丰富的可用特征突变体，使C。elegans是研究神经元发育的强大遗传模型。我们将首先研究已知的 肌动蛋白调节轴突导向和特定神经元中的突触发生。我们假设，肌动蛋白调节子的子集有一个独特的作用，无论是轴突的指导或突触，以及这些肌动蛋白调节子的差异调节和功能的基础上，在这两个过程中所涉及的不同肌动蛋白动力学。与此同时，我们将使用正向遗传学方法来识别新的基因，这些基因将突触图案线索与突触前F-肌动蛋白组装联系起来。最后，通过研究肌动蛋白调节剂和多个外在的线索，在一个单一的细胞介导轴突的指导和突触发生之间的遗传相互作用，我们将揭示这些线索如何收敛到调节肌动蛋白动力学。神经元中的异常肌动蛋白调节与许多神经系统疾病有关，包括帕金森病和自闭症。更全面地了解神经元中肌动蛋白调节的机制是设计有效治疗这些疾病的重要一步。