Role of axoglial CAMs in the organization of myelinated axons

轴胶质 CAM 在有髓轴突组织中的作用

• 批准号: 8788068
• 负责人: ELIOR PELES
• 金额: $ 16.72万
• 依托单位: WEIZMANN INSTITUTE OF SCIENCE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788068
• 关键词: Affect; Axon; Binding; Cell Adhesion Molecules; Cells; Cytoskeleton; Demyelinating Diseases; Demyelinations; Development; Disease; Exhibits; Fiber; Gene Targeting; Generations; Genes; Heparan Sulfate Proteoglycan; Human; Ion Channel; Lead; Mediating; Membrane; Molecular; Morphology; Movement; Multiple Sclerosis; Mus; Mutant Strains Mice; Myelin; Myelin Sheath; Nerve; Nerve Fibers; Nervous system structure; Neuroglia; Neurons; Nodal; Peripheral Nerves; Peripheral Nervous System; Phenotype; Physiological; Play; Positioning Attribute; Potassium Channel; Prevalence; Property; Proteins; Ranvier' s Nodes; Recruitment Activity; Research; Role; Route; Schwann Cells; Site; System; TAG-1 axonal glycoprotein; Testing; Transgenic Organisms; design; hereditary neuropathy; in vivo; mutant; research study; restoration; scaffold

DESCRIPTION (provided by applicant): The myelin sheath covers the axon in segments that are separated by the nodes of Ranvier. In the underlying axons Na+ channels are clustered at the nodes of Ranvier, separated by a specialized axoglial paranodal junction (PNJ) from K+ channels that are found at the nearby juxtaparanodal region (JXP). This organization is essential for the saltatory movement of the nerve impulses, and its disturbance results in pathophysiological changes often seen in demyelinating human disorders. In the peripheral nervous system (PNS), myelinating Schwann cells regulate this precise organization of the axonal membrane through unknown mechanisms. We have previously identified several cell adhesion molecules (CAMs), including gliomedin, Caspr, Caspr2, and Necl4, which mediate axoglial contact at specific sites along the longitudinal axis of the myelin unit. These CAMs play important roles in the organization of myelinated axons: gliomedin cluster Na+ channels at nodes, Caspr is involved in the generation of a membrane barrier at the PNJ that restricts the distribution of Na+ and K+ channels to the nodes and JXP, respectively, Caspr2 serves as a scaffold that maintains K+ channels at the JXP, and Necl proteins organize the internodal membrane. The objective of the proposed research is to study the molecular mechanisms underlying the function of these axoglial CAMs in the generation of functional domains along myelinated axons. First, complementation experiments will be carried out using myelinating Schwann cells/neuron cultures isolated from gldn-/- mice to determine how the channels clustering activity of gliomedin is being regulated. Secondly, a transgenic rescue approach will be taken to examine the hypothesis that the PNJ restricts the distribution of Na+ channels to the nodal gap by forming a membrane barrier, which depends on the presence of the axonal cytoskeleton. Third, a similar in vivo approach will be taken in order to examine the mode of interaction between Caspr2 and TAG-1 and to reveal the underlying mechanisms by which these molecules recruit and retain Kv1 channels at the JXP. Finally, we will study the role of Necl proteins in the organization of myelinated axons by analyzing the morphology and the molecular organization of peripheral nerves of mutant mice lacking Necl4, as well as mice lacking the cytoskeletal linker protein 4.1G, which colocalizes and associates with Necl4 in myelinating Schwann cells. Altogether, the proposed experiments will provide important information about the coordinated differentiation of axons and myelin-forming cells, which allow myelinated fibers to maximize their conduction velocity. Better understanding these mechanisms may thus lead to new routes to the restoration of function in demyelinated axons and may prove useful in the design of therapeutical strategies for demyelinating disorders.

描述（由申请人提供）：髓鞘覆盖由Ranvier结分开的轴突节段。在下面的轴突中，Na+通道聚集在Ranvier节点处，通过专门的轴神经节旁结（PNJ）与在附近的轴神经节旁结区域（JXP）发现的K+通道分开。这种组织对于神经冲动的跳跃运动是必不可少的，并且其干扰导致在脱髓鞘人类疾病中常见的病理生理学变化。在周围神经系统（PNS）中，髓鞘形成的许旺细胞通过未知的机制调节轴突膜的这种精确组织。我们以前已经确定了几种细胞粘附分子（CAM），包括胶质细胞介导蛋白，半胱氨酸蛋白酶抑制剂，Caspr 2，和Necl 4，介导轴胶质细胞接触在特定的网站沿着髓鞘单位的纵轴。这些CAM在有髓轴突的组织中起重要作用：神经胶质细胞调节蛋白簇Na+通道在节点处，Caspr参与PNJ处的膜屏障的产生，其分别限制Na+和K+通道分布到节点和JXP，Caspr 2充当维持JXP处的K+通道的支架，并且Necl蛋白组织结间膜。 该研究的目的是研究这些轴突胶质细胞CAM在沿着有髓鞘轴突产生功能域的分子机制。首先，将使用从gldn-/-小鼠分离的髓鞘形成施旺细胞/神经元培养物进行互补实验，以确定如何调节神经胶质调节素的通道聚集活性。其次，将采取转基因救援方法来检验PNJ通过形成膜屏障将Na+通道的分布限制在节间隙的假设，该膜屏障取决于轴突细胞骨架的存在。第三，将采取类似的体内方法，以检查Caspr 2和TAG-1之间的相互作用模式，并揭示这些分子在JXP招募和保留Kv 1通道的潜在机制。最后，我们将通过分析缺乏Necl 4的突变小鼠以及缺乏细胞骨架连接蛋白4.1G的小鼠的外周神经的形态学和分子组织来研究Necl蛋白在有髓轴突组织中的作用，所述细胞骨架连接蛋白4.1G在髓鞘形成的雪旺细胞中与Necl 4共定位并相关联。 总而言之，拟议的实验将提供有关轴突和髓鞘形成细胞协调分化的重要信息，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，从而可能导致新的途径，以恢复功能的脱髓鞘轴突，并可能证明是有用的脱髓鞘疾病的治疗策略的设计。

项目成果

Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B.

• DOI: 10.1523/jneurosci.5225-09.2010
• 发表时间: 2010-02-17
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Horresh I;Bar V;Kissil JL;Peles E
• 通讯作者: Peles E

A novel method for isolating Schwann cells using the extracellular domain of Necl1.

• DOI: 10.1002/jnr.21985
• 发表时间: 2009-11-15
• 期刊: JOURNAL OF NEUROSCIENCE RESEARCH
• 影响因子: 4.2
• 作者: Spiegel, Ivo;Peles, Elior
• 通讯作者: Peles, Elior

Identification of Tmem10/Opalin as an oligodendrocyte enriched gene using expression profiling combined with genetic cell ablation.

• DOI: 10.1002/glia.20688
• 发表时间: 2008-08-15
• 期刊: GLIA
• 影响因子: 6.2
• 作者: Golan, Neev;Adamsky, Konstantin;Kartvelishvily, Elena;Brockschnieder, Damln;Moebius, Wiebke;Spiegel, Ivo;Roth, Alejandro D.;Thomson, Christine E.;Rechavi, Gideon;Peles, Elior
• 通讯作者: Peles, Elior

The making of a node: a co-production of neurons and glia.

• DOI: 10.1016/j.conb.2013.06.003
• 发表时间: 2013-12
• 期刊: Current opinion in neurobiology
• 影响因子: 5.7
• 作者: Eshed-Eisenbach Y;Peles E
• 通讯作者: Peles E

Essential fnction of protein 4.1G in targeting of membrane protein palmitoylated 6 into Schmidt-Lanterman incisures in myelinated nerves

蛋白 4.1G 在将膜蛋白棕榈酰化 6 靶向有髓神经 Schmidt-Lanterman 切口中的基本功能

• DOI: 10.1128/mcb.05945-11
• 发表时间: 2012
• 期刊: Mol Cell Biol.
• 作者: Terada N;et.al
• 通讯作者: et.al