Mechanisms Differentiating Dendrite Development from Axon Development

描述(由申请人提供)： 我的职业目标是了解神经元区划的机制，以及这一过程如何有助于神经系统功能和神经系统疾病的发病机制。我将通过在一家学术机构担任独立调查员来追求这一目标。在加州大学旧金山分校Yeh Nung Jan博士的博士后培训期间，我一直在使用果蝇PNS神经元作为模型系统，研究树突和轴突的不同发育机制，轴突是神经元的两个主要部分。这次培训是对我脊椎动物神经生物学博士培训的补充。我计划结合果蝇的优势(体内和卓越的遗传学)和培养的大鼠海马神经元(特征良好的细胞生物学)来研究神经元的区划。本研究的目的是研究分泌途径在区分树突和轴突发育中的作用。从果蝇的遗传筛查中，我们分离到了几个突变体(DAR突变体)，它们的树突减少，但轴突正常。Dar2、Dar3和Dar6调节分泌途径，表明该途径区分树突状和轴突生长。我提出两个目标。首先，我将确定分泌途径不同地控制树突状和轴突生长的细胞生物学机制。将开发新的技术来补充现有的技术，以确定这种机制。通过分泌途径的膜运输将被监测在活的野生型和突变的果蝇胚胎/幼虫和培养的海马神经元中。其次，我将通过调节分泌途径的关键角色来识别和表征控制树突和轴突差异发育的基因。将研究Dar7(与dar2和3在基因上相互作用)、dar1(遗传相互作用未经测试)和拖尾连接(调节分泌途径)。他们的哺乳动物同源基因将在培养的神经元中进行检查，以确定这些机制在哺乳动物中是否保守。这项研究将为了解神经疾病的原因提供急需的信息，这些疾病的特征是优先损害树突(例如，Rett综合征)或高尔基体功能缺陷(例如，肌萎缩侧索硬化症)。这些信息还将使治疗方法的设计成为可能。

DESCRIPTION (provided by applicant): 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 (well- characterized 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), dar1 (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.