Molecular Characterization of Axon-Glial Interactions

轴突-神经胶质相互作用的分子表征

基本信息

批准号：
7590361
负责人：
MANZOOR A. BHAT
金额：
$ 25.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7590361
关键词：
Action Potentials Address Adherens Junction Affect Area Axon Binding Biochemical Biological Cell Aggregation Cell membrane Cells Complex Defect Demyelinating Diseases Development Disease Drosophila Nrx protein Drosophila Proteins Drosophila genus Drosophila inturned protein Ectopic Expression Electrons Embryo Embryonic Development Exhibits Fiber Figs - dietary Future Genetic Goals Homologous Gene Invertebrates Knockout Mice Maps Membrane Methods Molecular Mus Mutant Strains Mice Myelin Nerve Neuroglia Neurons Nodal Peripheral Peripheral Nerves Phenotype Play Potassium Channel Protein Binding Domain Protein Isoforms Proteins Research Personnel Role Septate Sequence Homology Staging Structure Structure-Activity Relationship Surface System Tight Junctions Transgenic Organisms Vertebrates Work contactin fly insight interest loss of function mutant neurofascin neuroglian neuronal survival novel paranodin programs

项目摘要

The molecular interactions between axons and glial cells constitute an area of immense interest. Many diseases produce their debilitating effects by altering the structural and functional relations between axons and glial cells, which in turn affect action potential propagation and even neuronal survival. In vertebrate myelinated axons, a structural specialization, the axo-glial septate junction (SJ), forms at the paranode between myelin loops and the axonal surface. Axo-glial SJs are characterized by ladder-like electron dense structures. Our recent work shows that axo-glial SJs are also present in Drosophila nerves. In addition to structural similarities, compelling molecular homologies are observed between axo-. glial SJs in fly and those in mouse. The Drosophila proteins: Neurexin (NRX), Contactin (CONT) and Neuroglian (NRG) form a tripartite complex that localizes to axo-glial SJs. Their murine homologs NCP1, Contactin and Neurofascin 155kDa isoform (NF155) also form a complex at axo- glial SJs. Our phenotypic analyses of Drosophila neurexin and mouse NCP1 mutants show that both mutants lack SJs. In this application, we propose to use genetic, cell biological, molecular and biochemical methods in Drosophila and mouse to address the following questions: (1) When do axo-glial SJs form during embryonic development in fly; Does axo-glial SJ formation coincide with the expression of NRX, CONT and NRG? Are axo-glial SJs absent in nrx, cont and nrg mutants? (2) What is the relationship of NRX, CONT and NRG to the formation of SJs in fly? Are NRX, CONT and NRG sufficient for the formation of SJs? (3) What is the loss of function phenotype of the mouse homolog of NRG (NF155)? What role does NF155 play in the formation of paranodal axo-glial SJs? Our studies will provide new insights into the mechanisms responsible for axon-glial interactions. In the future, these studies will advance our understanding of the functional deficits that accompany demyelinating disorders.

轴突和神经胶质细胞之间的分子相互作用构成了人们非常感兴趣的领域。许多疾病通过改变结构和功能关系来产生衰弱作用轴突和神经胶质细胞之间，进而影响动作电位传播，甚至神经元生存。在脊椎动物的有髓轴突中，轴突与胶质细胞间隔连接是一种结构特化 (SJ)，形成于髓磷脂环和轴突表面之间的旁节点。轴突神经胶质 SJ 是其特点是梯状电子致密结构。我们最近的工作表明轴神经胶质 SJ 果蝇神经中也存在。除了结构相似性之外，axo-之间还观察到令人信服的分子同源性。果蝇和小鼠中的神经胶质 SJ。果蝇蛋白：Neurexin (NRX)、Contactin (CONT) 神经胶质细胞 (NRG) 和神经胶质细胞 (NRG) 形成定位于轴神经胶质 SJ 的三联复合体。他们的鼠类同源物 NCP1、Contactin 和 Neurofascin 155kDa 同工型 (NF155) 也在 axo- 处形成复合物胶质SJ。我们对果蝇神经毒素和小鼠 NCP1 突变体的表型分析表明两种突变体都缺乏 SJ。在此应用中，我们建议使用遗传、细胞生物学、分子和生化方法果蝇和小鼠解决以下问题： (1)果蝇胚胎发育过程中轴神经胶质SJs何时形成；轴突胶质细胞SJ吗形成与NRX、CONT和NRG的表达一致？轴突神经胶质 SJ 是否缺失在 nrx、cont 和 nrg 突变体中？ (2) NRX、CONT、NRG与飞行中SJs的形成有何关系？是NRX， CONT 和 NRG 足以形成 SJ 吗？ (3) NRG (NF155)小鼠同系物的功能丧失表型是什么？什么角色 NF155 在节点旁轴突神经胶质 SJ 的形成中发挥作用吗？我们的研究将为轴突-神经胶质相互作用的机制提供新的见解。在未来，这些研究将增进我们对伴随而来的功能缺陷的理解脱髓鞘疾病。