Genetic Analysis of Glial Contribution to Peripheral Nervous System Assembly

描述(申请人提供)：运动神经扮演着将信息从中枢神经系统分流到外围目标的关键角色。它们的形成需要不同的细胞成分的协调发展，包括运动轴突和包裹它们的神经胶质细胞。在神经系统构建过程中，这些细胞必须长距离迁移并协调它们的分化，确保电信息的有效传播。为了更好地了解、诊断和治疗周围神经系统的许多退行性疾病，我们需要了解幼年和成年生物中介导神经发育和髓鞘维持的神经胶质相互作用的细胞和分子机制。斑马鱼提供了一个独特的机会，可以直接观察和操纵细胞群，以深入了解三叉神经节最初是如何建立、维持和在疾病期间的行为。在初步研究中，我们证明形成神经外膜的神经膜细胞起源于脊髓腹侧的神经胶质细胞，影响雪旺细胞的发育，对运动神经的发育是必不可少的。因此，在本项目的目标1中，我们将利用延时成像和基因操作来研究雪旺细胞和神经周围神经胶质细胞在神经组装过程中相互作用的假设。在目标2中，我们将鉴定两个新的突变系，它们在神经周围神经胶质发育方面存在缺陷，并鉴定与表型有关的突变基因。识别这些基因将为我们提供关于PNS形成所需的分子机制的额外信息。这些目标的完成将极大地扩展我们对调节周围神经发育的细胞和分子机制的了解，促进旨在治疗周围神经疾病的新的药物疗法。 公共卫生相关性：外周神经的一个或多个受损或功能失调的成分可导致外周疾病或损伤。虽然每种疾病的进展都是独一无二的，但最终结果是患者的生活质量大大降低。在这个项目中，我们将识别新的细胞行为和新的基因，这些是周围神经组装和维护所必需的。

DESCRIPTION (provided by applicant): Motor nerves play the critical role of shunting information out of the central nervous system to targets in the periphery. Their formation requires the coordinated development of distinct cellular components, including motor axons and the glial cells that ensheathe them. During nervous system construction, these cells must migrate long distances and coordinate their differentiation, ensuring the efficient propagation of electrical information. To better understand, diagnose and treat the many degenerative disorders of the peripheral nervous system, we need to comprehend the cellular and molecular mechanisms that mediate glial interactions along developing nerves and myelin maintenance in juvenile and adult organisms. Zebrafish provide a unique opportunity to directly observe and manipulate cell populations to gain insight into how the PNS is initially established, maintained and behaves during disease. In preliminary studies, we demonstrate that perineurial cells, which form the perineurium, originate as glial cells in the ventral spinal cord, influence Schwann cell development and are essential to motor nerve development. Therefore, in Aim 1 of this project, we will investigate the hypothesis that Schwann cells and perineurial glia reciprocally interact during nerve assembly by utilizing time-lapse imaging and genetic manipulation. In Aim 2, we will characterize two new mutant lines that have defects in perineurial glial development and identify the mutated genes responsible for the phenotypes. Identifying these genes will give us additional information about the molecular mechanisms necessary for PNS formation. Completion of these aims will greatly expand our knowledge of the cellular and molecular mechanisms that mediate peripheral nerve development, facilitating new drug therapies intended to treat peripheral neuropathies. PUBLIC HEALTH RELEVANCE: One or more damaged or dysfunctional components of peripheral nerves can result in peripheral disease or injury. Although the progression of each disorder is unique, the ultimate outcome is a greatly reduced quality of life for the afflicted individual. In this project, we will identify new cellular behaviors and novel genes that are necessary for peripheral nerve assembly and maintenance.