Molecular Characterization of Axon-Glial Interactions

轴突-神经胶质相互作用的分子表征

• 批准号: 7096271
• 负责人: MANZOOR A. BHAT
• 金额: $ 25.98万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/7096271
• 关键词: Chordata; Drosophilidae; axon; flying; mutant; myelin; proteins

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（由申请人提供）：轴突和神经胶质细胞之间的分子相互作用构成了一个非常感兴趣的领域。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产生其衰弱效应，这反过来又影响动作电位传播甚至神经元存活。在脊椎动物有髓轴突中，结构特化，即轴-胶质分隔连接（SJ），形成于髓鞘环和轴突表面之间的旁阳极。轴神经胶质细胞的特点是电子致密的梯形结构。我们最近的工作表明，轴胶质细胞SJS也存在于果蝇神经。除了结构上的相似性，引人注目的分子同源性之间观察到的轴神经胶质细胞的SJS在苍蝇和小鼠。果蝇蛋白：Neurexin（NRX）、Contactin（CONT）和Neuroglian（NRG）形成定位于轴胶质SJS的三重复合物。它们的鼠同源物NCP 1、接触蛋白和神经成束蛋白155 kDa同种型（NF 155）也在轴神经胶质SJS处形成复合物。我们对果蝇neurexin和小鼠NCP 1突变体的表型分析表明，这两种突变体都缺乏SJS。 在本申请中，我们建议在果蝇和小鼠中使用遗传学、细胞生物学、分子和生物化学方法来解决以下问题： (1)果蝇胚胎发育过程中轴胶质细胞SJ何时形成;轴胶质细胞SJ的形成与NRX、CONT和NRG的表达是否一致？在nrg、nrg和nrg突变体中是否缺少轴胶质细胞SJS？ (2)NRX、CONT和NRG与果蝇SJS的形成有什么关系？NRX、CONT和NRG是否足以形成SJS？ (3)什么是NRG（NF 155）小鼠同源物的功能丧失表型？NF 155在结旁轴胶质细胞SJS的形成中起什么作用？ 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脱髓鞘疾病伴随的功能缺陷的理解。