Molecular Organization & Function of Paranodal Junctions

描述：细胞间连接在细胞中扮演着重要的角色 增殖、细胞间屏障的形成、分化与组织 形态发生。此外，它们还保持组织的结构完整性， 也是信号转导的中心。我们已经刻画了 果蝇神经毒素IV(NRX IV)，并表明该蛋白是 神经胶质细胞-神经胶质隔膜连接的形成。这些交汇点非常关键 用于维持血脑屏障和隔离轴突 对抗血淋巴。NRX IV功能丧失导致隔膜丧失 神经胶质细胞之间的连接，从而导致血脑屏障的破坏。 在脊椎动物中，间隔连接只存在于有髓神经纤维中。 它们被组织成解剖和生理上截然不同的纵向 域：节间、邻域、副域和结点。 这些结构的形成和组织是由一系列 分子事件，包括不同物种的迁移、重新定位和聚集 蛋白质进入特定的结构域。 分隔状的连接出现在副电极上，并提供了 轴突和神经胶质细胞之间的粘连。他们还用栅栏限制了 电压门控Na+和延迟整流K+通道 分别集中在结节和毗邻结节区域。复合体 轴突和髓鞘胶质细胞之间的分子相互作用是必不可少的。 通过跳跃传导实现神经冲动的快速传导。我们有 鉴定了果蝇NRX IV的小鼠同源物MNCP(MNRX IV/CASPR/Paranodin)，表明MNCP的亚细胞分布为 发育受调控，MNCP定位于偏阳极 与结旁交界处的形成相吻合。MNCP无效鼠标显示 严重的神经缺陷，出生后3-4周内死亡。损失 MNCP的作用会导致横带或间隔连接的丢失 并引起结节形态异常。在这笔赠款中，我们建议 使用遗传、分子和生化方法的组合来解决 以下问题：1)什么分子事件参与了黑洞的形成 结旁间隔连接及MNCP在这些连接形成中的作用 连接？2)隔膜的形成和功能需要哪些基因 果蝇的交界处？和3)什么是细胞外配体/受体01 神经胶质细胞表面的MNCP以及哪些细胞内伙伴 与MNCP在旁结节交界处关联？这些研究应该会有所帮助 了解这个高度保守的蛋白质家族的功能，并提供 对隔膜生物发生机制的新认识 从果蝇到人类的连接。

DESCRIPTION: Intercellular junctions play an important role in cell proliferation, intercellular barrier formation, differentiation and tissue morphogenesis. In addition they maintain structural integrity of the tissues, and also serve as centers for signal transduction. We have characterized Drosophila Neurexin IV (NRX IV) and showed that this protein is required for the formation of glial-glial septate junctions. These junctions are critical for the maintenance of the blood-brain barrier and for insulation of axons against the hemolymph. Loss of function of NRX IV resulted in loss of septate junctions between glial cells and hence, breakdown of the blood-brain barrier. In vertebrates, septate junctions are present only in myelinated nerve fibers which are organized into anatomically and physiologically distinct longitudinal domains: the internode, the juxtaparanodes, the paranodes and the node. The formation and organization of these structures results from a sequence of molecular events including migration, relocalization and clustering of various proteins into specific domains. The septate-like junctions are present at the paranodes and provide a site of adhesion between the axons and glial cells. They also fence the distribution of voltage gated Na+ and delayed rectifier K+ channels which are highly concentrated in the nodal and juxtaparanodal regions, respectively. Complex molecular interactions between axons and myelinating glial cells are essential for the rapid conduction of nerve impulses via saltatory conduction. We have identified the mouse homolog of Drosophila NRX IV, MNCP (for MNRX IV/Caspr/Paranodin) and show that the subcellular distribution of MNCP is developmentally regulated, and that the MNCP localization to paranodes coincides with the formation of paranodal junctions. MNCP null mice display severe neurologic defects, and die postnatally within 3-4 weeks. Loss of function of MNCP results in loss of transverse bands or septate junctions at the paranodes and causes abnormal nodal morphology. In this grant we propose to use a combination of genetic, molecular and biochemical methods to address the following questions: 1) What molecular events are involved in the formation of paranodal septate junctions and what role MNCP plays in the formation of these junctions? 2) What genes are required for the formation and function of septate junctions in Drosophila? And 3) What are the extracellular ligands/receptors 01 MNCP on the glial surface and what are the intracellular partners that associate with MNCP at the paranodal junctions? These studies should help understand the function of this highly conserved protein family, and provide new insights into the mechanisms that govern the biogenesis of septate junctions from Drosophila to human.