Identification, Development and Function of Rapidly Adapting Mechanoreceptors

触觉，包括对形状和质地的感知，是我们日常生活中必不可少的 活着。三叉神经节和背根神经节(DRG)神经元亚群是主要的 参与这一过程的感觉神经元，分为快速(RA)或 缓慢适应(SA)机械感受器。它们的分子身份，独特的功能 形式和质地感知的背景以及发展的机制在很大程度上 未知。最近，我发现一小部分DRG神经元表达 受体酪氨酸激酶Ret是难以捉摸的RA机械受体，Ret 信号对它们的发育是必不可少的。在此应用程序中，我建议进行以下实验 阐明Ret和TrkB信号控制生存、外周血细胞的机制 类风湿关节炎的终末器官形成、中枢投射和生理特性 机械感受器。此外，我还建议发展新的触觉辨别行为 用体感神经元特异性白喉毒素(DTA)小鼠品系进行检测 RA机制受体在触觉辨别过程中的体内功能。 具体目标1：检验Ret和TrkB对于肺癌生存是多余的假设 RA机械感受器及其TrkB在RA机械感受性背根节神经元中的作用 自主形成迈斯纳小体。在这个目标中，Ret和TrkB加倍 将生成基因敲除小鼠和TrkB条件基因敲除小鼠来测试我的 假设。 具体目标2：解决Ret信号导向中枢的机制 RA机械感受器的投射。为此，我将视觉化中央轴突 个体Ret Null RA机械感受器在发育早期的投射 确定初级轴突投射缺陷的性质。此外，我还将确定 Ret的内源性配体和共受体及其来源，以建立 作用机制。 具体目标3：确定Ret信号是否调节生理 类风湿关节炎机械感受器的特性。在这一目标中，RA的生理特性 机械感受器，其中Ret在发育早期或急性消融 成人的激活或抑制将被检查。 目的4：研究RA机械受体在体内的功能作用。至 研究各种机械感受器的独特功能，我将开发新的行为 测试小鼠的触觉辨别能力。另外，我还会产生一种体感 神经元特异性条件性DTA小鼠品系。总而言之，这些新的分析和试剂 将使我能够解决RA机械感受器的作用，并在未来的其他 触觉辨别过程中背根神经节神经元的数量。

Touch sensation, including the perception of form and texture, is essential for our daily lives. Subpopulations of trigeminal and dorsal root ganglion (DRG) neurons are primary sensory neurons mediating this process, and are classified as either rapidly (RA) or slowly adapting (SA) mechanoreceptors. Their molecular identities, unique functions in the context of form and texture perception, and mechanisms of development are largely unknown. Recently, I discovered that a small population of DRG neurons that express the receptor tyrosine kinase Ret are the elusive RA mechanoreceptors and that Ret signaling is essential for their development. In this application, I propose experiments to elucidate the mechanisms by which Ret and TrkB signaling control survival, peripheral end organ formation, central projections, and physiological properties of RA mechanoreceptors. In addition, I propose to develop new tactile discrimination behavior assays and a somatosensory neuron specific diphtheria toxin (DTA) mouse line to test the in vivo functions of RA mechaoreceptors during tactile descrimination. Specific Aim 1: To test the hypothesis that Ret and TrkB are redundant for survival of RA mechanoreceptors and that TrkB functions in RA mechanosensory DRG neurons autonomously for Meissner corpuscle formation. In this aim, Ret and TrkB double knock out mice and TrkB conditional knock out mice will be generated to test my hypothesis. Specific Aim 2: To address the mechanism by which Ret signaling directs central projections of RA mechanoreceptors. For this purpose, I will visualize the central axonal projections of individual Ret null RA mechanoreceptors during early development to establish the nature of the primary axonal projection deficit. In addition, I will identify the endogenous ligand and co-receptor of Ret, and their sources, to establish the mechanism of action. Specific Aim 3: To determine whether Ret signaling modulates the physiological properties of RA mechanoreceptors. In this aim, physiological properties of RA mechanoreceptors in which Ret is either ablated early during development or acutely activated or inhibited in adults will be examined. Aim 4: To begin to establish the functional roles of RA mechanoreceptors in vivo. To study the unique functions of various mechanoreceptors, I will develop new behavioral assays to test tactile discrimination in mice. In addition, I will generate a somatosensory neuron specific conditional DTA mouse line. Together, these new assays and reagent will enable me to address the role of RA mechanoreceptors and, in the future additional populations of DRG neurons during tactile discrimination.