Identification, Development and Function of Rapidly Adapting Mechanoreceptors

触觉，包括对形状和质地的感知，对我们的日常生活至关重要。 生活三叉神经和背根神经节（DRG）神经元的亚群是主要的 感觉神经元介导这一过程，并被分类为快速（RA）或 缓慢适应（SA）机械感受器。它们的分子特性， 形式和质地感知的背景，以及发展的机制， 未知最近，我发现一小群DRG神经元表达 受体酪氨酸激酶Ret是难以捉摸RA机械受体，Ret 信号对它们的发育至关重要。在这个应用中，我提出了实验， 阐明Ret和TrkB信号转导控制生存、外周血淋巴细胞增殖和凋亡的机制。 RA的终末器官形成、中枢投射和生理特性 机械感受器此外，我建议开发新的触觉辨别行为 测定和体感神经元特异性白喉毒素（DTA）小鼠系来测试 RA机械感受器在触觉识别中的体内功能。 具体目标1：检验Ret和TrkB对于小鼠的存活率是多余的这一假设。 RA机械感受性神经元中TrkB的功能 自主地形成迈斯纳小体。为此，Ret和TrkB加倍 将产生敲除小鼠和TrkB条件性敲除小鼠以测试我的 假说. 具体目标2：解决Ret信号传导指导中枢神经系统的机制。 RA机械感受器的投射。为此，我将可视化中央轴突 在早期发育过程中，单个Ret无效RA机械感受器的投射 确定原发性轴突投射缺陷的性质。此外，我将确定 Ret的内源性配体和共受体，以及它们的来源，以建立 作用机制。 具体目标3：确定Ret信号传导是否调节生理性 RA机械感受器的性质。在这个目标中，RA的生理特性 Ret在发育早期或急性期被消融的机械感受器 将检查成人中激活或抑制的。 目的4：开始建立RA机械感受器在体内的功能作用。到 研究各种机械感受器的独特功能，我将开发新的行为 在小鼠中测试触觉辨别的试验。另外，我会产生一个体感 神经元特异性条件DTA小鼠系。总之，这些新的测定和试剂 将使我能够解决RA机械感受器的作用，并在未来的其他 在触觉辨别过程中的DRG神经元群体。

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.