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。尽管这些轴突的皮肤末梢通常只占外周轴突总长度的一小部分，但它们对功能至关重要，因为它们是首次检测到触摸刺激的部位。皮肤轴突末梢特别容易受到损伤、糖尿病和遗传性综合征（特别是腓骨肌萎缩症）的损害。所有这些情况都会导致衰弱的周围神经病变，其特征是慢性疼痛或无法感知触觉。因此，了解皮肤感觉末梢是如何形成、维持和对损伤作出反应的，对于理解这些疾病和开发有效的治疗方法至关重要。我们开发了一个幼体斑马鱼模型来研究体感觉外周轴突和它们支配的皮肤细胞的发育。由于斑马鱼的幼虫是外部受精的，发育迅速，并且光学清晰，因此斑马鱼的体感系统为研究皮肤神经支配的早期阶段提供了无与伦比的实验途径。相比之下，研究哺乳动物的这些皮肤感觉终端是具有挑战性的，因为它们是在子宫内发育的，而且它们完整的三维结构很难可视化。从鱼类到哺乳动物，皮肤中体感觉轴突区域的大多数解剖和分子特征都保存得很好，这使得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表明，皮肤细胞在皮肤体感轴突末端的发育、修复和功能中起着几个关键作用。这一建议的目标是识别和表征轴突和皮肤细胞之间的分子对话，这些对话调节体感觉轴突区域的建立和维持。利用我们近年来开发的一套独特而强大的分子技术和转基因工具，我们将研究在体感觉神经元个体发生的特定阶段轴突/皮肤相互作用的性质的三个问题。首先，感觉轴突是如何被引导到皮肤上的？第二，一旦进入皮肤，轴突是如何在结构上与皮肤细胞联系起来的？第三，皮肤是如何对轴突损伤做出反应并促进修复的？我们将通过实时成像、胚胎学和分子摄动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几个调控

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.