GABAERGIC NEURON DIFFERENTIATION IN C ELEGANS

描述形态，连接正确的突触伙伴，并选择 他们的神经递质是理解神经递质的基本问题 神经系统的形成和功能。 复杂性和难度 在高等生物体中， 阐明这种机制的实验障碍。 单纯的神经质 线虫C.秀丽线虫在解剖学上有很好的特征， 提供了一个很好的实验模型，以解决每个事件的神经元 体内连接形成与单细胞分辨率。 研究者 已经鉴定出unc-30，一种同源结构域蛋白，作为 控制19个GABA能神经元的终末分化。 损失 UNC-30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。 为了确定在这些神经元中起作用的其他基因， 在分化中，申请人研究了潜在的靶基因unc-25， unc-30，编码谷氨酸脱羧酶（GAD）， 在这些神经元中产生GABA。 这项工作是唯一的例子， GAD在遗传学上被定义为多细胞生物，并且是GAD的调节因子。 GAD已识别。 这项建议的主要目的是剖析整个 这些GABA能的终末分化的分子遗传学程序 神经元 有几种方法将被用来确定参与这一过程的基因。 过程，例如分离功能获得性突变体的抑制子， unc-30和unc-30弱等位基因的显性增强子，以及分离 差异表达的mRNA。 许多试剂和突变体 已经确定，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能 C. elegans是特定的。 GABA是主要的抑制剂， 所有动物体内的神经递质 GABA能神经元功能异常， 与几种人类疾病有关 这项工作可能会提供见解 对基本机制的理解， 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.