GABAERGIC NEURON DIFFERENTIATION IN C ELEGANS

描述形态，连接正确的突触伙伴，并选择 它们的神经递质是理解 神经系统的形成和功能。复杂性和艰巨性 高等生物体中单个神经元的可及性是主要的 阐明这种机制的实验障碍。单纯的紧张 线虫系统具有良好的解剖学特征和 提供了一个出色的实验模型来处理神经元的每个事件 以单细胞分辨率在体内形成连接。调查员 已经确定UNC-30是一种同源结构域蛋白，是 控制19个GABA能神经元的终末分化。损失 UNC-30的功能导致这些神经元不能正确分化 缺乏GABA；UNC-30的异位表达将其他细胞转化为 GABA能神经元。以确定在这些神经元中起作用的其他基因 分化，申请人已经研究了UNC-25，一个潜在的目标基因 UNC-30，编码谷氨酸脱羧酶(GAD)，负责 在这些神经元中产生GABA。这项工作是其中唯一的例子 GAD是从基因上定义的多细胞生物体，是GAD的调节因子 GAD已被确认。这项提案的主要目的是剖析 这些赤霉菌末端分化的分子遗传程序 神经元。将使用几种方法来识别与此相关的基因 过程，如分离功能获得突变体的抑制子 UNC-30和UNC-30弱等位基因显性增强子的分离 差异表达的mRNAs。许多试剂和突变体都有 已确定以帮助深入分析这些功能 基因。该提案还包括分析其他类型的GABA如何 线虫中的神经元是特定的。GABA是主要的抑制因子 所有动物体内的神经递质。GABA能神经元功能异常 与几种人类疾病有牵连。这项工作可能会提供一些见解 对于理解在精确度基础上的基本机制 所有生物体中的神经元连接和神经元类型的多样化。

DESCRIPTION morphology, connect with correct synaptic partners, and choose their neurotransmitters are fundamental questions for understanding the formation and function of a nervous system. The complexity and difficulty in accessibility to individual neurons in higher organisms are major experimental obstacles for elucidating such mechanisms. The simple nervous system of the nematode C. elegans is well characterized anatomically and offers an excellent experimental model to address each event of neuronal connection formation in vivo with single cell resolution. The investigator has identified unc-30, a homeodomain protein, as the key regulator in controlling the terminal differentiation of 19 GABAergic neurons. Loss of unc-30 function causes these neurons to fail to differentiate properly and to lack GABA; ectopic expression of unc-30 transforms other cells into GABAergic neurons. To identify other genes that function in these neurons' differentiation, the applicant has studied unc-25, a potential target gene of unc-30, that encodes glutamic acid decarboxylase (GAD) and is responsible for producing GABA in these neurons. This work is the only example among multicellular organisms that GAD is defined genetically and a regulator of GAD is identified. The main aim of this proposal is to dissect the complete molecular genetic program of the terminal differentiation of these GABAergic neurons. Several approaches will be used to identify genes involved in this process, such as isolation of suppressors of gain-of-function mutants of unc-30 and dominant enhancers of a weak allele of unc-30, and isolation of differentially expressed mRNAs. A number of reagents and mutants have already been identified to help analyze in depth the function of these genes. The proposal also includes analysis of how other types of GABAergic neurons in C. elegans are specified. GABA is the major inhibitory neurotransmitter in all animals. Abnormal GABAergic neuron function has been implicated in several human diseases. This work may provide insights to the understanding of basic mechanisms underlying the precision of neuronal connections and diversification of neuronal types in all organisms.