Pheromone sensing in mammals

描述(申请人提供)：这项申请是为了更新研究，旨在了解介导小鼠嗅觉交流的分子和细胞事件，特别是那些潜在的复杂社会行为，如攻击性、母性关怀和交配。大多数哺乳动物的化学感觉是通过至少两个不同的鼻部组织实现的：主嗅觉上皮(MOE)和犁鼻器(VNO)。在过去的两年里，旨在了解VNO在嗅觉通讯和信息素感知中的作用的研究激增，但一个关键问题仍然存在：犁鼻感觉神经元(VSNs)信号转导机制的本质是什么？这个应用程序的目标1就是围绕这个问题。与此同时，越来越多的证据表明，MOE中的感觉神经元可能对哺乳动物的信息素交流也至关重要。这些细胞的身份和它们的信号机制尚不清楚。AIM 2解决了这个问题。我们的主要目标是通过确定VNO和MOE中信息素感知的细胞和分子机制来缩小我们知识中的这些关键差距。为了达到这一目标，我们将在目标1中重点研究VSNs信息素转导的一个重要组成部分，瞬时受体电位(Trp)通道TRPC2。这项应用的一个主要目的将是了解激活和调节TRPC2形成的通道的潜在机制，利用一种独特的靶向缺失TRPC2基因的敲除小鼠。色氨酸通道基因家族的成员最近已经成为各种感觉系统的重要组成部分，包括味觉、热感和平衡感。因此，我们的结果应该对更好地理解不同感觉模式的编码和转导策略具有普遍意义。在目标2中，我们将重点研究MOE中一个神秘的感觉神经元亚群的功能，即GC-D细胞，它表达膜鸟苷环化酶GC-D和其他几种蛋白质，这些蛋白质使人想起cGMP依赖的转导途径。我们将首次系统分析GC-D细胞的生理特性，包括它们对化学感觉配体的反应，利用基因靶向小鼠，这些小鼠既破坏编码GC-D的基因，又用报告基因特异性标记GC-D细胞。具体地说，我们将测试这一假设，即GC-D细胞系统作为信息素检测系统发挥作用，这是检测有限的生物相关化学信号所必需的。

DESCRIPTION (provided by applicant): This application is for renewal of research directed toward understanding the molecular and cellular events that mediate olfactory communication in mice, specifically those events underlying complex social behaviors such as aggression, maternal care, and mating. Chemosensation in most mammals is achieved by at least two distinct nasal tissues: the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). The past two years have seen an explosion of studies aimed at understanding the role of the VNO in olfactory communication and pheromone sensing, but a key question remains: What is the nature of the signal transduction mechanism in vomeronasal sensory neurons (VSNs)? Aim 1 of this application is centered on this question. At the same time, evidence is accumulating that sensory neurons in the MOE may also be crucial for pheromone communication in mammals. The identity of the cells and their signaling mechanisms are obscure. Aim 2 addresses this problem. Our main goal is to narrow these critical gaps in our knowledge by determining the cellular and molecular mechanisms that underlie pheromone sensing in the VNO and MOE. To reach this goal we will focus in Aim 1 on an essential component of pheromone transduction in VSNs, the transient receptor potential (TRP) channel TRPC2. A major aim of this application will be to understand the mechanisms underlying activation and regulation of the channels formed by TRPC2, taking advantage of a unique knockout mouse with a targeted deletion in the TRPC2 gene. Members of the TRP channel gene family have recently emerged as essential components in a variety of sensory systems including the senses of taste, heating and balance. Therefore, our results should be of general interest for a better understanding of coding and transduction strategies across different sensory modalities. In Aim 2, we will focus on the function of an enigmatic subpopulation of sensory neurons in the MOE known as GC-D cells, which express the membrane guanylyl cyclase GC-D and several other proteins reminiscent of a cGMP-dependent transduction pathway. We will provide the first systematic analysis of the physiological properties of GC-D cells, including their responses to chemosensory ligands, taking advantage of gene targeted mice that both disrupt the gene that encodes GC-D and specifically label the GC-D cells with a reporter. Specifically, we will test the hypothesis that the GC-D cell system functions as a pheromone detection system necessary for the detection of a limited set of biologically relevant chemical signals.