Investigating the role of a conserved serine/threonine kinase, SAX-1, in higher-order dendrite pruning

项目摘要 神经突重塑是一个高度保守的过程，完善和建立一个成熟的神经系统。故障 神经突重塑导致神经和神经发育障碍。发育树突状细胞 修剪是神经突重塑的一种手段，已被广泛研究， 控制修剪仍然知之甚少。具体来说，在理解神经元如何 可以选择性地修剪特定的树枝，同时保持姐妹枝完整。长期目标是 识别和理解指导分支特异性修剪的细胞生物学机制。线虫 秀丽隐杆线虫内唇2（IL 2）神经元在进入发育滞育后， 当发育恢复时被修剪的典型的树突乔木-留下完整的初级树突。的 IL-2神经元的刻板重塑允许实验进入阐明细胞生物学机制 赋予选择性修剪。中心假设是SAX-1，一种进化上转化的丝氨酸/苏氨酸， 激酶，在一个分子途径中起作用，该途径将钙信号传导与细胞骨架动力学以更高的顺序联系起来 树枝状分支直接选择性修剪。提出这一建议的理由是，研究SAX-1的作用 在IL 2重塑过程中，将提供一个框架，以了解细胞骨架的局部调节如何赋予 枝特异性修剪中心假设将通过以下具体目标进行检验：1）确定如何 SAX-1指导高级IL 2树突分支的修剪;和2）鉴定其中SAX-1表达的遗传途径。 1在修剪过程中调节细胞骨架。这项研究提案是创新的，因为它将1）是 首先建立C. 2）阐明了SAX-1在植物修剪中的新作用， 树突修剪，和3）确定如何在修剪过程中局部调节细胞骨架。拟议 研究是重要的，因为阐明了分支特异性的基本细胞生物学机制， 修剪将大大推进我们对发育神经突重塑的理解。这种理解是 这是一个关键，它告诉我们神经发育过程是如何在唐氏综合症等疾病中出错的。

PROJECT SUMMARY Neurite remodeling is a highly conserved process that refines and establishes a mature nervous system. A failure in neurite remodeling leads to neurological and neurodevelopmental disorders. While developmental dendritic pruning, a means of neurite remodeling, has been extensively studied, the cell-biological mechanisms that control pruning remain poorly understood. Specifically, there is a fundamental gap in understanding how neurons can selectively prune specific dendritic branches while leaving sister branches intact. The long-term goal is to identify and understand the cell-biological mechanisms that direct branch-specific pruning. The nematode Caenorhabditis elegans inner labial 2 (IL2) neurons, upon entering a developmental diapause, extend a stereotypical dendritic arbor that is pruned when development is resumed – leaving primary dendrites intact. The stereotypic remodeling of IL2 neurons allows experimental access to elucidate the cell-biological mechanisms that confer selective pruning. The central hypothesis is that SAX-1, an evolutionarily conversed serine/threonine kinase, functions in a molecular pathway that links calcium signaling to cytoskeletal dynamics in higher-order dendrite branches to direct selective pruning. The rationale for this proposal is that studying the role SAX-1 during IL2 remodeling will offer a framework to understand how local regulation of the cytoskeleton confers branch-specific pruning. The central hypothesis will be tested by the following specific aims: 1) determine how SAX-1 directs pruning of higher-order IL2 dendrite branches; and 2) identify the genetic pathway in which SAX- 1 acts to regulate the cytoskeleton during pruning. The research proposal is innovative because it will 1) be the first to establish C. elegans as a model system for studying pruning, 2) elucidate a novel role for SAX-1 in dendritic pruning, and 3) determine how the cytoskeleton is locally regulated during pruning. The proposed research is significant because elucidating the fundamental cell-biological mechanisms of branch-specific pruning will significantly advance our understanding of developmental neurite remodeling. This understanding is a critical to inform us about how neurodevelopmental processes go awry in disorders such as Down Syndrome.