Peripheral Territory Establishment By Zebrafish Somatosensory Neurons

斑马鱼体感神经元的外周区域建立

• 批准号: 9521182
• 负责人: Alvaro Sagasti
• 金额: $ 2.92万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9521182
• 关键词: 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine; Actins; Address; Adopted; Adult; Anatomy; Animals; Architecture; Axon; Binding; Biochemical; Biological Assay; Cells; Charcot-Marie-Tooth Disease; Collagen; Complex; Cutaneous; Cytoskeleton; Data; Defect; Development; Diabetes Mellitus; Dimensions; Disease; EXT2 gene; Eating; Embryo; Embryology; Embryonic Development; Enzymes; Event; Fishes; Glycoproteins; Goals; Growth; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Human; Image; Inherited; Injury; Instruction; Invertebrates; Larva; Length; Leukocytes; Light; Maintenance; Mammals; Modeling; Molecular; Morphogenesis; Morphology; Mosaicism; Natural regeneration; Nature; Nervous system structure; Neuroglia; Neurons; Optics; Peripheral; Peripheral Nervous System Diseases; Phagocytes; Phagocytosis; Phosphatidylinositols; Play; Presynaptic Terminals; Process; Production; Protein Tyrosine Phosphatase; Reagent; Regulation; Role; Sensory; Signal Transduction; Site; Skin; Specificity; Stereotyping; Stimulus; Structure; Syndrome; System; Techniques; Testing; Tissues; Touch sensation; Transgenic Organisms; Traumatic injury; Wallerian Degeneration; Zebrafish; apical membrane; axon growth; axon injury; axon regeneration; axonal degeneration; cell behavior; chronic pain; effective therapy; experimental study; gain of function; in utero; injured; insight; loss of function; nerve supply; nervous system disorder; painful neuropathy; programs; public health relevance; receptor; repaired; seal; somatosensory; three dimensional structure; time use; tool

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.

描述（由申请人提供）：体感神经元在发育早期将周围轴突投射到皮肤以检测触摸刺激。尽管这些轴突的皮肤末端通常只占外周轴突总长度的一小部分，但它们对于功能至关重要，因为它们是首先检测到触摸刺激的部位。皮肤轴突末端特别容易受到损伤、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。因此，表征皮肤感觉末梢如何形成、维持和对损伤的反应对于了解这些病症和开发有效的治疗方法至关重要。我们开发了斑马鱼幼虫模型来研究体感外周轴突及其神经支配的皮肤细胞的发育。由于斑马鱼幼虫在体外受精、发育迅速且光学透明，斑马鱼体感系统为了解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末梢具有挑战性，因为它们是在子宫内发育的，并且它们完整的三维结构很难可视化。从鱼类到哺乳动物，皮肤体感轴突区域的大多数解剖学和分子特征都得到了很好的保存，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、修复和功能中发挥着几个关键作用。该提案的目标是识别和表征轴突和皮肤细胞之间的分子对话，这些对话调节体感轴突区域的建立和维护。使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，我们将研究关于体感神经元个体发育特定阶段轴突/皮肤相互作用性质的三个问题。首先，感觉轴突如何引导至皮肤？其次，一旦进入皮肤，轴突如何在结构上与皮肤细胞相关？第三，皮肤如何应对轴突损伤并有助于修复？我们将通过实时成像、胚胎学和分子扰动的强大结合来解决这些问题。总的来说，这些研究将为数种调控提供第一个分子洞察。 新发现的皮肤细胞在体感系统发育和维护中的功能。