Molecular Organization & Function of Paranodal Junctions

描述：细胞间连接在细胞内起着重要作用。 增殖、细胞间屏障形成、分化和组织 形态发生此外，它们保持组织的结构完整性， 也是信号传导的中心。我们有特点 果蝇Neurexin IV（NRX IV），并表明这种蛋白质是 胶质细胞间隔膜连接的形成。这些连接点至关重要 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，从而破坏血脑屏障。 在脊椎动物中，分隔连接只存在于有髓神经纤维中 其被组织成解剖学上和生理学上不同的纵向 区域：节间、腹节、腹节和节。 这些结构的形成和组织是由一系列 分子事件，包括迁移、重新定位和聚集， 蛋白质进入特定区域。 隔膜样连接存在于副阳极，并提供了一个位点， 轴突和神经胶质细胞之间的粘附。他们还为分发 电压门控Na+和延迟整流K+通道，其高度依赖于细胞膜。 分别集中在结节区和非结节区。复杂 轴突和髓鞘神经胶质细胞之间的分子相互作用是必不可少的 用于通过跳跃式传导快速传导神经冲动。我们有 鉴定了果蝇NRX IV的小鼠同源物，MNCP（用于MNRX IV/Caspr/Paranodin），并显示MNCP的亚细胞分布是 发育调节，并且MNCP定位于paranodes 与结旁连接的形成相吻合MNCP敲除小鼠显示 严重的神经系统缺陷，并在出生后3-4周内死亡。损失 MNCP的功能导致横带或分隔连接的丢失， 并导致异常的结节形态。在这一补助金中，我们建议 使用遗传、分子和生物化学方法的组合来解决 以下问题：1）什么分子事件参与形成 结旁分隔连接，以及MNCP在这些连接的形成中起什么作用 连接点？2)分隔细胞的形成和功能需要哪些基因 果蝇的连接点和3）什么是细胞外配体/受体01 神经胶质细胞表面的MNCP和什么是细胞内的合作伙伴， 在结旁连接处与MNCP有联系吗这些研究应该有助于 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 果蝇与人类的连接点

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.