Mechanisms Differentiating Dendrite Development from Axon Development

我的职业目标是了解神经元区划的机制以及这个过程是如何 有助于神经系统功能和神经系统疾病的发病机制。我会追查下去的 目标是以独立调查员的身份在学术机构工作。在我的博士后培训期间 加州大学旧金山分校Yeh Nung Jan博士的实验室，我一直在使用果蝇三叉神经节神经元作为模型系统 研究树突和轴突两个主要亚室发育的区别机制 一个神经元的。这次培训是对我脊椎动物神经生物学博士培训的补充。我计划将两者结合起来 果蝇(体内和卓越的遗传学)和培养的大鼠海马神经元(特性良好)的强度 细胞生物学)来研究神经元的区划。 本研究的目的是研究分泌途径在树突分化中的作用。 和轴突发育。从果蝇的遗传筛查中，我们分离出了几个突变体(DAR突变体)， 树枝减少，但轴突正常。Dar2、Dar3和Dar6调节分泌途径，提示 这一途径区分了树突和轴突的生长。我提出两个目标。首先，我将确定单元格 分泌途径不同地控制树突状和轴突的生物学机制 成长。将开发新的技术来补充现有的技术，以确定这种机制。 将监测活的野生型和突变型果蝇通过分泌途径的膜运输 胚胎/幼虫和培养的海马神经元。第二，我将识别和描述那些 通过调节分泌的关键分子控制树突和轴突的分化发育 路径。DAR7(与DAR2和DAR3在基因上相互作用)、DARL(基因相互作用未经测试)和拖车挂钩 (调节分泌途径)将被研究。他们在哺乳动物中的同源物将在培养的 以确定这种机制在哺乳动物中是否保守。 这项研究将为理解神经性疾病的原因提供急需的信息 以树突优先受损为特征的疾病(例如，雷特氏综合征)或高尔基体缺陷 功能(例如，肌萎缩侧索硬化症)。这样的信息也将允许设计治疗 接近了。

My career goal is to understand the mechanisms of neuronal compartmentalization and how this process contributes to nervous system function and to the pathogenesis of neurological disorders. I will pursue this goal by working in an academic institution as an independent investigator. During my postdoctoral training in the laboratory of Dr. Yuh Nung Jan at UCSF, I have been using Drosophila PNS neurons as a model system to study the mechanisms that differentiate the development of dendrite from axon, two major compartments of a neuron. This training complements my doctoral training in vertebrate neurobiology. I plan to combine the strength of Drosophila (in vivo and superb genetics) and cultured rat hippocampal neurons (wellcharacterized cell biology) to study neuronal compartmentalization. The objective of this research is to examine the roles of the secretory pathway in differentiating dendrite and axon development. From a genetic screen in Drosophila, we isolated several mutants (dar mutants) with reduced dendritic arbors but normal axons. Dar2, 3, and 6 regulate the secretory pathway, suggesting that this pathway differentiates dendritic and axonal growth. I propose two aims. First, I will determine cell biological mechanisms through which the secretory pathway differentially controls dendritic and axonal growth. New techniques will be developed to complement existing ones to identify such mechanisms. Membrane traffic through the secretory pathway will be monitored in live wild-type and mutant Drosophila embryos/larvae and cultured hippocampal neurons. Second, I will identify and characterize genes that control the differential development of dendrites and axons by regulating key players of the secretory pathway. Dar7 (genetically interacts with dar2 and 3), darl (genetic interaction untested), and Trailer Hitch (regulates the secretory pathway) will be studied. Their mammalian homologs will be examined in cultured neurons to determine if the mechanisms are conserved in mammals. This research will provide much-needed information for understanding the causes of neurological disorders characterized by preferential damage to dendrites (e.g., Rett's syndrome) or by defective Golgi function (e.g., amyotrophic lateral sclerosis). Such information will also allow the design of therapeutic approaches.