Peripheral Territory Establishment By Zebrafish Somatosensory Neurons

描述（由申请人提供）：体感神经元在发育早期将外周轴突投射到皮肤以检测触摸刺激。虽然这些轴突的皮肤末梢通常是总外周轴突长度的比例小的组成部分，但它们对于功能是至关重要的，因为它们是首先检测到触摸刺激的部位。皮肤轴突末梢特别容易受到损伤、糖尿病和遗传综合征（尤其是腓骨肌萎缩症）的损害。所有这些病症都会导致以慢性疼痛或无法感知触觉为特征的衰弱性周围神经病变。因此，表征皮肤感觉末梢是如何形成、维持和对损伤作出反应的，对于理解这些病症和开发有效的治疗方法至关重要。我们建立了一个斑马鱼幼鱼模型来研究躯体感觉外周轴突和它们所支配的皮肤细胞的发育。由于斑马鱼幼体是外部受精，发育迅速，光学清晰，斑马鱼体感系统提供了无与伦比的实验进入皮肤神经支配的早期阶段。相比之下，在哺乳动物中研究这些皮肤感觉末梢是具有挑战性的，因为它们在子宫内发育，并且它们的完整三维结构难以可视化。从鱼类到哺乳动物，皮肤中体感轴突领土的大多数解剖学和分子特征都很好地保存下来，使斑马鱼成为揭示潜在疾病机制的相关模型。我们过去几年的研究已经揭示，皮肤细胞在皮肤中的体感轴突终末的发育、修复和功能中起着几个关键作用。这项建议的目标是确定和表征轴突和皮肤细胞之间的分子对话，调节建立和维持体感轴突领土。使用一套独特的和强大的分子技术和转基因工具，我们已经在最近几年开发的，我们将调查三个问题的轴突/皮肤的相互作用的性质在特定阶段的体感神经元个体发育。首先，感觉轴突是如何被引导到皮肤的？第二，一旦进入皮肤，轴突是如何与皮肤细胞在结构上联系起来的？第三，皮肤如何应对轴突损伤并有助于修复？我们将通过活体成像、胚胎学和分子微扰的有力结合来解决这些问题。总的来说，这些研究将提供第一个分子洞察到几个调节 新发现的功能皮肤细胞的发展和维持的躯体感觉系统。

DESCRIPTION (provided by applicant): Somatosensory neurons project peripheral axons to the skin early in development to detect touch stimuli. Although the cutaneous terminals of these axons are often a proportionally small component of the total peripheral axon length, they are critical for function, since they are the sites where touch stimuli are first detected. Cutaneous axon endings are particularly vulnerable to damage by injury, diabetes, and inherited syndromes, notably Charcot-Marie-Tooth diseases. All of these conditions cause debilitating peripheral neuropathies characterized by chronic pain or the inability to sense touch. Characterizing how cutaneous sensory endings are formed, maintained, and respond to injury is thus essential for understanding these conditions and developing effective treatments. We have developed a larval zebrafish model to study the development of somatosensory peripheral axons and the skin cells that they innervate. Because zebrafish larvae are fertilized externally, develop rapidly, and are optically clear, the zebrafish somatosensory system offers unparalleled experimental access to the early stages of skin innervation. By contrast, studying these cutaneous sensory terminals in mammals is challenging, since they develop in utero and their complete three-dimensional structures are difficult to visualize. Most anatomical and molecular features of somatosensory axon territories in the skin are well conserved from fish to mammals, making zebrafish a relevant model for uncovering potential disease mechanisms. Our studies of the past few years have revealed that skin cells play several critical roles in the development, repair and function of somatosensory axon terminals in the skin. The goal of this proposal is to identify and characterize the molecular dialogues between axons and skin cells that regulate the establishment and maintenance of somatosensory axon territories. Using a unique and powerful set of molecular techniques and transgenic tools that we have developed in recent years, we will investigate three questions about the nature of axon/skin interactions during specific stages of somatosensory neuron ontogeny. First, how are sensory axons guided to the skin? Second, once in the skin how do axons become structurally associated with skin cells? And third, how does the skin respond to axon damage and contribute to repair? We will address these questions with a powerful combination of live imaging, embryology and molecular perturbations. Collectively, these studies will provide the first molecular insight into the regulation of several newly discovered functions of skin cells in the development and maintenance of the somatosensory system.