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

项目总结 轴突重塑是一个高度保守的过程，可以提炼和建立成熟的神经系统。一次失败 轴突重塑会导致神经和神经发育障碍。而发育中的树突 修剪，一种重塑轴突的方法，已经被广泛研究，细胞生物学机制 对照修剪仍然知之甚少。具体地说，在理解神经元是如何 可以选择性地修剪特定的树枝，同时保持姊妹枝的完整。长期目标是 确定和理解指导特定枝条修剪的细胞生物学机制。线虫 秀丽线虫内唇2(IL2)神经元，在进入发育滞育时，延长 当发育恢复时被修剪的刻板的树状乔木--保持初级树突完好无损。这个 IL2神经元的刻板重塑为阐明细胞生物学机制提供了实验途径 这赋予了选择性修剪的权利。中心假设是SAX-1，一种进化上转换的丝氨酸/苏氨酸 激酶在一条分子通路中发挥作用，该通路以更高的顺序将钙信号与细胞骨架动力学联系起来 树枝分枝到直接选择性修剪。这项提议的基本原理是研究SAX-1的作用 在IL2重塑过程中，将提供一个框架，以了解细胞骨架的局部调控是如何 特定于枝条的修剪。中心假设将通过以下具体目标进行检验：1)确定如何 SAX-1指导更高级别的IL2树突分支的修剪；以及2)鉴定SAX-1的遗传途径。 1在修剪过程中起到调节细胞骨架的作用。这项研究提案具有创新性，因为它将是 首先建立线虫作为研究修剪的模式系统，2)阐明SAX-1在剪枝中的新作用 树突修剪，以及3)确定细胞骨架在修剪过程中如何局部调节。建议数 这项研究具有重要意义，因为它阐明了枝条特异的基本细胞生物学机制 修剪将极大地促进我们对发育性轴突重塑的理解。这种理解是 这是告诉我们唐氏综合症等疾病的神经发育过程是如何出错的关键。

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.