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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：
7214057
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/7214057
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 Knock-out Localized Maps Membrane Methods Molecular Mus Mutant Strains Mice Myelin Nerve Neuroglia Neurons Nodal Numbers 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 contactins fly insight interest loss of function mutant neurofascin neuroglian neuronal survival novel paranodin programs

项目摘要

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：轴突和神经胶质细胞之间的分子相互作用构成了一个极具吸引力的领域。许多疾病通过改变轴突和神经胶质细胞之间的结构和功能关系而产生衰弱效应，进而影响动作电位的传播，甚至神经元的存活。在脊椎动物的有髓轴突中，在髓鞘环和轴突表面之间的副阳极处形成了一种结构特化，即轴突-神经胶质间隔连接(SJ)。轴-胶质SJS具有梯状电子致密结构。我们最近的工作表明，果蝇的神经中也存在轴突胶质细胞。除了结构上的相似性外，在苍蝇和小鼠的轴突胶质细胞SJS之间还观察到了令人信服的分子同源性。果蝇的三种蛋白质：Neuresin(NRX)、Contactin(Cont)和Neuroglian(NRG)形成了一个定位于轴突胶质细胞的三元复合体。它们的小鼠同系物NCP1、Contactin和NeuroFasin 155 kDa亚型(NF155)也在轴突-神经胶质SJS形成了一个复合体。我们对果蝇和小鼠NCP1突变体的表型分析表明，这两个突变体都缺乏SJS。在这一应用中，我们建议使用遗传学、细胞生物学、分子和生化方法在果蝇和小鼠身上解决以下问题： (1)果蝇胚胎发育过程中轴突形成的时间是否与NRX、CONT和NRG的表达相一致？NRX、CONT和NRG突变体中是否缺少轴突胶质细胞SJS？ (2)NRX、CONT、NRG与果蝇SJS的形成有何关系？NRX、CONT和NRG是否足以形成SJS？ (3)NRG(NF155)小鼠同源基因的功能缺失表型是什么？NF155在结旁轴突形成中起什么作用？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，这些研究将促进我们对伴随脱髓鞘障碍而来的功能缺陷的理解。