Genetic Dissecting Serotonergic Phenotypes in C elegans

线虫血清素能表型的基因剖析

• 批准号: 7289075
• 负责人: JI Y SZE
• 金额: $ 18.7万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7289075
• 关键词: Genetic; Dissecting; Serotonergic; Phenotypes; elegans

DESCRIPTION (provided by applicant): During the terminal differentiation, every neuron must choose a transmitter. Many different neurons choose the same transmitter, thus the same neurotransmitter may subserve many different functions. Although factors regulating early stages of neurogenesis are beginning to be elucidated, the genetic network determining neurotransmitter phenotypes is largely unknown.This proposal uses genetic approaches to identify genes determining the serotonergic phenotype and to study the role of serotonergic neurons in metabolic control in C. elegans. The proposed experiments take advantages that serotonin-deficient worms are fully viable, and the serotonergic system, including 5 classes, a total of 9 neurons, offers both the simplicity and diversity for genetic and physiological analysis.First, we will identify genes regulating serotonergic neuron development. We have isolated 2 classes of mutations affecting the development of particular serotonergic neurons. We will assess if the mutations prevent the neuron generation, or if they affect particular aspects of the final neuronal identity. We will clone 2-3 genes likely acting in the terminal differentiation and determine their expression pattern. Second, we will determine if there are cell-specific regulators directing serotonin synthesis. Through molecular dissection of the promoter of the serotonin synthetic enzyme gene tph-1, we will determine if discrete sequence motifs direct tph-1 expression in particular neurons. We will test if the POU-transcription factor UNC-86 that is required for tph-1 expression in a subset of the serotonergic neurons directly regulates tph-1. Third, we will assess the role of serotonergic neurons in metabolic control. Our previous study indicated that serotonin regulates the TGF-b and insulin neuroendocrine pathways to modulate C. elegans metabolism. We will test if mutations affecting particular serotonergic neurons affect a specific metabolic regulatory pathway, and if restoration of serotonin production in particular neurons rescues the metabolic defects of serotonin deficient mutants. Fourth, We will use genetic epistasis analysis to assess the interaction of serotonin and other neural signaling that also regulate metabolism. The goal is to explore how serotonin signals are integrated to modulate metabolism.Dysregulations of serotonin signaling have been associated with eating disorders, type II diabetes, and obesity. Identification of genes that determine the serotonergic phenotype and understanding the role of serotonergic neurons in the regulation of metabolism in C. elegans will provide reagents to study the development and function of serotonergic neurons in human.

描述（由申请人提供）：在终端分化期间，每个神经元必须选择发射器。许多不同的神经元选择相同的发射器，因此相同的神经递质可能会保留许多不同的功能。尽管调节神经发生早期阶段的因素已开始阐明，但确定神经递质表型的遗传网络在很大程度上是未知的。该提案使用遗传方法来识别确定血清素神经元在leeleansc。Elexagansc。ElexabolicC. e exelean氏菌中的基因确定基因。提出的实验具有缺乏5-羟色胺的蠕虫完全可行的优势，其中包括5个类别（总共9个神经元）提供的血清素能系统提供了遗传和生理分析的简单性和多样性。我们已经孤立了两类的突变，影响了特定的血清素能神经元的发展。我们将评估突变是否阻止神经元的产生，还是影响最终神经元认同的特定方面。我们将克隆2-3个可能作用于末端分化的基因并确定其表达模式。其次，我们将确定是否存在指导5-羟色胺合成的细胞特异性调节剂。通过5-羟色胺合成酶基因TPH-1的启动子的分子解剖，我们将确定离散序列是否在特定神经元中直接TPH-1表达。我们将测试在血清素能神经元中TPH-1表达所需的POU转录因子UNC-86是否直接调节TPH-1。第三，我们将评估血清素能神经元在代谢控制中的作用。我们先前的研究表明，血清素调节TGF-B和胰岛素神经内分泌途径来调节秀丽隐杆线虫的代谢。我们将测试影响特定血清素能神经元的突变是否影响特定的代谢调节途径，以及尤其是神经元的血清素产生的恢复是否会挽救5-羟色胺缺乏突变体的代谢缺陷。第四，我们将使用遗传性上毒分析来评估5-羟色胺和其他调节代谢的神经信号传导的相互作用。目的是探索如何整合5-羟色胺信号以调节代谢。5-羟色胺信号传导与饮食失调，II型糖尿病和肥胖有关。确定确定血清素能表型的基因，并了解血清素能神经元在秀丽隐杆线虫中代谢中的作用，将提供试剂以研究人类中血清素能神经元的发育和功能。