Genetic Analysis of Peripheral Nerve Development

描述(申请人提供)：本项目的学期目标是对脊椎动物周围神经形成的细胞和分子机制有一个全面而详细的了解。在发育过程中，中枢神经系统(CNS)和身体之间通过外周神经建立了许多联系。这些神经负责在两个方向上传递信息。一些神经将信号从中枢神经系统传递到身体，以控制运动和自主神经功能，而另一些神经则将有关外部刺激的信息从身体传递到中枢神经系统。未能正确形成或维持周围神经会导致大量的周围神经病变，表现为肌肉无力和肌肉控制丧失，胃肠功能障碍，无法感知疼痛或体温变化和神经性疼痛。我们研究周围神经发育的方法是创造转基因斑马鱼，在周围神经的不同细胞成分中表达荧光蛋白，然后在体内将延时成像与基因功能测试相结合。在初步研究中，我们确定神经周细胞在有髓运动神经周围形成保护鞘，起源于腹侧脊髓的神经胶质细胞，它们是运动神经发育所必需的。在本项目的具体目标1中，我们将研究特定的腹侧脊髓前体细胞发育为神经周细胞的分子机制。在特定的目标2中，我们将研究神经周围神经胶质细胞和雪旺细胞在运动神经形成中的作用。在特定的目标3中，我们将表征破坏雪旺细胞发育和髓鞘形成的突变，以此作为识别运动神经形成所必需的基因的一种方式。这些目标的完成将极大地扩展我们对周围神经发育中细胞行为和基因功能的理解，促进旨在治疗周围神经疾病的有效治疗设计。公共卫生相关性：未能正确形成或维持周围神经会导致大量的周围神经病变，表现为肌肉无力和肌肉失去控制、胃肠功能障碍、无法感知疼痛或体温变化以及神经性疼痛。该项目将确定周围神经发育所必需的细胞行为和基因。

DESCRIPTION (provided by applicant): The term goal of this project is to produce a comprehensive and detailed understanding of the cellular and molecular mechanisms that guide formation of peripheral nerves in vertebrates. During development, numerous connections are established between the central nervous system (CNS) and the body via peripheral nerves. These nerves are responsible for conveying information in two directions. Some nerves carry signals out of the CNS to the body to control movement and autonomic functions whereas other nerves transmit information about external stimuli from the body to the CNS. Failure to properly form or maintain peripheral nerves results in a large array of peripheral neuropathies that are manifested as, for example, muscle weakness and loss of muscle control, gastrointestinal dysfunction, inability to sense pain or change in temperature and neuropathic pain. Our approach to investigating peripheral nerve development is to create transgenic zebrafish that express fluorescent proteins in different cellular components of peripheral nerves and then combine in vivo, time-lapse imaging with tests of gene function. In preliminary studies we determined that perineurial cells, which form a protective sheath around myelinated motor nerves, originate as glial cells in the ventral spinal cord and that they are essential to motor nerve development. In Specific Aim 1 of this project we will investigate the molecular mechanisms that specify ventral spinal cord precursors to develop as perineurial cells. In Specific Aim 2 we will investigate the roles of perineurial glia and Schwann cells in motor nerve formation. In Specific Aim 3 we will characterize mutations that disrupt Schwann cell development and myelination as a way to identify genes that are necessary for motor nerve formation. Completion of these aims will greatly extend our understanding of both cellular behavior and gene function in peripheral nerve development, facilitating effective design of therapy intended to treat peripheral neuropathies. PUBLIC HEALTH RELEVANCE: Failure to properly form or maintain peripheral nerves results in a large array of peripheral neuropathies that are manifested as, for example, muscle weakness and loss of muscle control, gastrointestinal dysfunction, inability to sense pain or change in temperature and neuropathic pain. This project will identify cellular behaviors and genes that are necessary to peripheral nerve development.