Mechanisms of pheromone signal transduction in C. elegans

描述（由申请人提供）：信息素作为短期嗅觉线索，表明危险或配偶的存在，以及通过调节神经内分泌轴介导发育和生理变化的长期线索。在哺乳动物中，信息素信号被转导来调节神经激素信号的机制知之甚少，尽管这种信号的失调会导致发育和行为障碍。嗅觉信号转导机制在生物体中是高度保守的，神经元传递机制也是如此，这表明在模式生物中研究这些过程可能为高等生物的相关过程提供见解。在秀丽隐杆线虫中，信息素通过调节激素信号来调节进入交替发育阶段，并为探索信息素信号如何被识别和转导以控制关键发育决策提供了一个很好的模型系统。最近在秀丽隐杆线虫中发现了结构相关的含有大量信息素的蛔虫苷，以及在秀丽隐杆线虫中发现的前两种信息素受体，其突变体在信息素介导的激素信号调节中存在缺陷，这在其他模式生物中仍然难以捉摸。本提案的目标是确定信息素信号转导所需的其他受体，并表征神经元间信息素信号传递所需的基因。这项工作将有助于我们理解信息素调节关键行为和发育决策的途径，以及这些途径的功能障碍如何导致发育受损、行为障碍和肥胖。建议的具体目标是：1。阿斯卡罗苷C3信号转导所需神经元和受体的鉴定。2. 细胞间信息素信号通路的鉴定。

DESCRIPTION (provided by applicant): Pheromones act as both short-term olfactory cues that signal danger or the presence of mates, as well as long-term cues, which mediate changes in development and physiology via modulation of the neuroendocrine axis. Little is known about the mechanisms by which pheromone signals are transduced to modulate neurohormonal signaling in mammals, although dysregulation of this signaling can result in developmental and behavioral disorders. Olfactory signal transduction mechanisms are highly conserved across organisms, as are mechanisms of neuronal transmission, indicating that studying these processes in model organisms may provide insights into related processes in higher organisms. In C. elegans, the dauer pheromone regulates entry into the alternate dauer developmental stage via regulation of hormonal signaling, and provides an excellent model system in which to explore how pheromone signals are recognized and transduced to govern a critical developmental decision. The recent identification of both the structurally related ascarosides comprising dauer pheromone in C. elegans, and the first two pheromone receptors in C. elegans, whose mutants are defective in pheromone-mediated regulation of hormonal signaling, remains elusive in other model organisms. The goal of this proposal is to identify additional receptors required for pheromone signal transduction, and to characterize a gene required for inter-neuronal pheromone signal transmission. This work will contribute to our understanding of the pathways by which pheromones regulate critical behavioral and developmental decisions, and how dysfunction of these pathways can lead to impaired development, behavioral disorders, and obesity. The proposed specific aims are: 1. Identification of the neurons and receptors required for C3 ascaroside signal transduction ascaroside. 2. Identification of intercellular pheromone signaling pathways. PUBLIC HEALTH RELEVANCE: Pheromones are secreted molecules that communicate immediate and long-term signals among animals of the same species. For a complete understanding of how humans smell, and how odors affect development and behavior, a thorough understanding of the mechanisms of detecting and relaying pheromonal signals is necessary. This work will lead to a better understanding of how the brain processes chemical signals, and how dysfunction of the chemosensory system leads to impaired development, behavioral disorders, and obesity.