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（申请人提供）：在终末分化过程中，每个神经元必须选择一个递质。许多不同的神经元选择相同的递质，因此相同的神经递质可以实现许多不同的功能。虽然调控神经发生早期阶段的因素已开始阐明，但决定神经递质表型的遗传网络在很大程度上是未知的。优美的该实验利用了昆虫能神经元缺乏的优势，以及昆虫能神经元系统（包括5类共9个神经元）的简单性和多样性，为遗传学和生理学分析提供了便利。首先，我们将鉴定调节昆虫能神经元发育的基因。我们已经分离出2类影响特定多巴胺能神经元发育的突变。我们将评估突变是否阻止神经元的产生，或者它们是否影响最终神经元身份的特定方面。我们将克隆2-3个可能在终末分化中起作用的基因，并确定它们的表达模式。其次，我们将确定是否有细胞特异性调节剂指导血清素的合成。通过对5-羟色胺合成酶基因tph-1启动子的分子解剖，我们将确定离散序列基序是否指导tph-1在特定神经元中的表达。我们将测试是否POU-转录因子的tph-1的表达所需的一个子集的多巴胺能神经元直接调节tph-1。第三，我们将评估肾上腺素能神经元在代谢控制中的作用。我们以前的研究表明，5-羟色胺通过调节TGF-β和胰岛素神经内分泌通路来调节C。elegans代谢我们将测试影响特定的5-羟色胺能神经元的突变是否会影响特定的代谢调节途径，以及特定神经元中5-羟色胺产生的恢复是否会挽救5-羟色胺缺陷突变体的代谢缺陷。第四，我们将使用遗传上位性分析来评估5-羟色胺和其他调节代谢的神经信号的相互作用。目的是探索5-羟色胺信号是如何整合来调节新陈代谢的。5-羟色胺信号调节异常与饮食失调、II型糖尿病和肥胖有关。确定决定肾上腺素能表型的基因，并了解肾上腺素能神经元在C. elegans将为研究人类多巴胺能神经元的发育和功能提供试剂。