Genetic Analysis of Glial Contribution to Peripheral Nervous System Assembly

描述（由申请人提供）：运动神经在将信息从中枢神经系统分流到外周目标的过程中起着关键作用。它们的形成需要不同细胞成分的协调发育，包括运动轴突和包裹它们的神经胶质细胞。在神经系统的构建过程中，这些细胞必须长距离迁移并协调它们的分化，以确保电信息的有效传播。为了更好地理解、诊断和治疗周围神经系统的许多退行性疾病，我们需要了解在幼年和成年生物体中，介导神经发育和髓磷脂维持过程中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PNS最初是如何建立、维持和在疾病期间的行为的。在初步研究中，我们证明形成会神经膜的会神经细胞起源于脊髓腹侧的胶质细胞，影响雪旺细胞的发育，对运动神经的发育至关重要。因此，在本项目的目的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胶质细胞在神经组装过程中相互作用的假设。在Aim 2中，我们将描述两种新的突变系，它们在神经周围胶质细胞发育中存在缺陷，并确定导致表型的突变基因。识别这些基因将为我们提供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介导周围神经发育的细胞和分子机制的认识，促进旨在治疗周围神经病变的新药物治疗。

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.