Genetic Dissection of Serotonergic Phenotypes in C. elegans

描述(申请人提供)：在脊椎动物和无脊椎动物中，5-羟色胺(5-羟色胺)信号调节大量的行为和生理过程。5-羟色胺表型复杂性的遗传基础和分子机制尚不清楚。因此，阐明调节5-羟色胺神经元发育和功能的基因和分子机制将有助于深入了解神经元多样性的原理，揭示神经系统和生理在分子和细胞水平上的相互作用。利用复杂的线虫遗传学，我们独特的突变体，以及允许在活动物的单细胞分辨率下定量测量5HT产生的分子标记，我们正在对5HT系统进行遗传解剖，检验一个中心假说：不同神经元中的5HT产生受不同转录因子的调节，并受到不同机制的调节，以响应不同的内部和外部环境刺激，以辅助不同的生理功能。这项提议有四个具体目标。(1)通过对我们收集的突变体和RNA干扰筛选的遗传作图，我们将定义新的基因，这些基因指定5HT的身份，并调节已识别的神经元中5HT的产生。(2)利用抑制子遗传学，我们将跟随我们的发现，在一对5HT神经元的感觉末端的Trp通道通过定义与该通道相互作用并作用于该通道下游的组件来控制5HT的产生。(3)使用分子、细胞和行为方法，我们将把这样识别的基因组织成分子和细胞途径。(4)使用我们已建立的范式，我们将测试特定的5HT神经元中的特定信号级联是否调节特定的行为，以及它们是否控制不同的应激反应路径。针对5-羟色胺系统的药物是治疗抑郁症和许多行为和神经精神障碍的最常用的处方药。在模型生物体中识别调节5-羟色胺信号的基因和生化途径将导致有吸引力的新候选对象在与疾病的关联研究中进行测试，可能导致新的诊断方法和新的药物。

DESCRIPTION (provided by applicant): In both vertebrates and invertebrates, serotonin (5HT) signaling regulates a vast array of behavior and physiological processes. The genetic basis and molecular mechanisms underlying the complexity of 5HT phenotypes are not well understood. Thus elucidation of genes and molecular mechanisms that regulate the development and function of 5HT neurons will provide insights into the principles of neuronal diversity and reveal reciprocal effects of the nervous system and physiology at molecular and cellular levels. Taking the advantage of sophisticated C. elegans genetics, our unique mutants, and molecular markers that allow a quantifiable measure of 5HT production at the resolution of single cells in living animals, we are undertaking genetic dissection of the 5HT system, testing a central hypothesis: 5HT production in different neurons is regulated by different transcription factors and is modulated by different mechanisms in response to different internal and external environmental stimuli to subserve different physiological functions. This proposal has four specific objectives. (1) By genetic mapping of our collected mutants and RNA-interference screens, we will define new genes that specify 5HT identity and that regulate 5HT production in identified neurons. (2) Using suppressor genetics, we will follow our discovery that a TRP channel at the sensory ending of a pair of 5HT neurons controls 5HT production by defining components that interact with and that act downstream of the channel. (3) Using molecular, cellular, and behavioral approaches, we will organize so identified genes into molecular and cellular pathways. (4) Using our established paradigms, we will test whether specific signaling cascades in specific 5HT neurons modulate specific behavior and if they control distinct stress responsive pathways. Drugs that target the 5HT system are the most commonly prescribed therapeutics for the treatment of depression and many behavioral and neuropsychiatric disorders. Identification of genes and biochemical pathways that regulate 5HT signaling in a model organism will lead to compelling new candidates to be tested in association studies with the diseases, potentially leading to novel diagnostics and new medications.