Role of three novel CAMs in myelinating glia

描述(申请人提供)：髓鞘神经胶质细胞与其潜在轴突之间的相互作用将Ranvier结节及其周围的轴索膜组织成不同的区域，每个区域包含一组独特的离子通道、细胞黏附分子和细胞质适配器蛋白。轴突的这种局部分化对于动作电位的快速有效传播是必不可少的，它的破坏导致了常见于脱髓鞘疾病的病理生理变化。本研究计划确定髓鞘雪旺细胞(SC)调节Ranvier结节建立的分子机制。我们最近发现了三个新的胶质细胞黏附分子，Gliomedin，CDO和Zig1，它们定位于接触Ranvier结节的SC微绒毛。此外，我们还发现Gliomedin是长期以来一直被追捧的神经胶质细胞黏附分子NrCAM和NeuroFascin的受体，这两种细胞黏附分子与结节轴膜上的Na+通道有关。 我们建议确定这些胶质细胞CaM介导的轴突-神经胶质接触是否控制着沿着轴突膜的Na+通道的聚集。首先，这些蛋白质在发育过程中的分布将被检查，并与节点的分子组装相关。其次，我们将使用体外髓鞘形成系统以及通过分析通过基因打靶消除Gliomedin、CDO或Zig1的小鼠来确定它们在髓鞘形成和Ranvier结节形成中的作用。最后，将采用生化和分子相结合的方法来揭示这些神经胶质细胞在结节上所介导的分子相互作用。我们的研究将对轴突-神经胶质通讯以及轴突和髓鞘形成细胞的协调分化机制产生重要的见解，这使得有髓纤维能够最大限度地提高其传导速度。更好地了解这些机制可能有助于设计未来脱髓鞘障碍的治疗策略。

DESCRIPTION (provided by applicant): The interaction between myelinating glial cells and their underlying axons organize the axonal membrane at and around the nodes of Ranvier into distinct domains, each of which contains a unique set of ion channels, cell adhesion molecules and cytoplasmic adaptor proteins. This local differentiation of the axon is essential for the fast and efficient propagation of action potentials and its disruption results in pathophysiological changes often seen in demyelinating diseases. This research proposal sets out to identify the molecular mechanisms by which myelinating Schwann cells (SC) regulate the establishment of the nodes of Ranvier. We have recently identified three novel glial cell adhesion molecules (glial CAMs), Gliomedin, CDO and Zig1 that are localized at the SC microvilli which contact the nodes of Ranvier. Furthermore, we have found that Gliomedin is the long sought-after glial receptor for NrCAM and neurofascin, two cell adhesion molecules that are associated with Na+ channels at the nodal axolemma. We propose to determine whether axon-glial contact mediated by these glial CAMs controls the clustering of Na+ channels along the axonal membrane. First, the distribution of these proteins during development will be examined and correlated with the molecular assembly of the nodes. Secondly, we will determine their role in myelination and the formation of the nodes of Ranvier using an in vitro myelination system, as well as by analyzing mice in which Gliomedin, CDO or Zig1 have been eliminated by gene targeting. Finally, a combined biochemical and molecular approach will be taken to reveal the molecular interactions mediated by these glial CAMs at the nodes. Our studies will yield important insight into the yet elusive mechanisms of axon-glial communication and the coordinated differentiation of axons and myelin-forming cells, which allows myelinated fibers to maximize their conduction velocity. A better understanding of these mechanisms may help to design future therapeutical strategies for demyelinating disorders.