Investigating Glial Interactions Across the Motor Exit Point During Development

 描述(申请人提供)：发展一个有功能和高效的神经系统需要轴突及其相关神经胶质细胞的有计划的迁移和分化。运动轴突将中枢神经系统(CNS)与包括肌肉在内的外周靶点连接起来。这些轴突与中枢神经系统和周围神经系统(PNS)中的髓鞘胶质细胞相互作用。最终，这两个不同的胶质细胞群体的分化形成了一个特殊的结构，称为过渡区(TZ)，它存在于脊髓和周围之间的每一个边界上。有趣的是，在运动出口点(MEP)TZS，少突胶质细胞和外周髓鞘胶质细胞通常局限于各自的神经系统，而其他胶质细胞，包括神经周围胶质细胞和一种新描述的细胞群MEP胶质细胞，可以自由地从脊髓向外迁移。MEP TZs是如何选择性渗透的，限制髓鞘细胞混合，同时允许其他群体通过，目前尚不清楚。在这个项目中，我们将描述一种新的胶质细胞群体--运动出口点(MEP)胶质细胞的发育和功能，我们证明这种细胞对于将少突胶质细胞前体细胞(OPC)限制到脊髓是必不可少的(目标1)。在AIM 2，我们将采用候选和无偏倚的方法，研究MEP胶质细胞-OPC在发育过程中相互作用的分子机制。沿着轴突发育或维持髓鞘的缺陷是许多统称为髓鞘病的疾病的原因，Charcot-Marie-Tooth病(CMT)就是这样一个例子。一些最严重的这种疾病会导致儿童脱髓鞘、神经变性和随后的肌肉萎缩。利用活体系统斑马鱼，直接研究建立MEP TZS的胶质-神经胶质相互作用，我们将为功能神经系统如何组装、维护和在疾病期间的行为提供重要的见解。

 DESCRIPTION (provided by applicant): Development of a functional and efficient nervous system requires the orchestrated migration and differentiation of axons and their associated glia. Motor axons connect the central nervous system (CNS) with targets in the periphery, including muscle. These axons interact with myelinating glial cells both in the CNS and peripheral nervous system (PNS). Ultimately, the differentiation of these two distinct glial populations forms a specialized structure known as the transition zone (TZ), which exists at every boundary between the spinal cord and periphery. Interestingly, at motor exit point (MEP) TZs, oligodendrocytes and peripheral myelinating glia normally stay restricted to their respective half of the nervous system, while other glia, including perineurial glia and a newly described population of cells, MEP glia, freely migrate from the spinal cord out into the periphery. How MEP TZs are selectively permeable, restricting myelinating cells from mixing, while allowing the passage of other populations, is unknown. In this project, we will characterize the development and function of a novel population of glia, motor exit point (MEP) glia, that we demonstrate are essential for restricting oligodendrocyte progenitor cells (OPC) to the spinal cord (Aim 1). In Aim 2, using both a candidate and unbiased approach, we will investigate the molecular mechanism that mediates MEP glia-OPC interactions during development. Defects in the development or maintenance of myelin along axons are the cause of many disorders collectively known as myelinopathies, one such example being Charcot-Marie-Tooth Disease (CMT). Some of the most severe types of this disease lead to demyelination, neurodegeneration and subsequent muscle atrophy in young children. Utilizing an in vivo system, zebrafish, to directly investigate the glial-glial interactions that establish MEP TZs, we will provide important insights into how functional nervous systems are assembled, maintained and behave during disease.