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引起关注的领域。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的作用，这反过来影响动作电位传播甚至神经元的生存。在脊椎动物髓鞘的轴突中，在髓磷酸环和轴突表面之间的偏执量处形成了结构专业化的轴突圆形分隔连接（SJ）。 Axo-Glial SJ的特征是类似梯子的电子致密结构。我们最近的工作表明，果蝇神经中也存在Axo-Glial SJ。除结构相似性外，在苍蝇中的轴 - 胶质SJ和小鼠中的轴向胶质SJ之间还观察到了引人注目的分子同源性。果蝇蛋白：Neurexin（NRX），Contactin（续）和Neuroglian（NRG）形成了一种定位于Axo-Glial SJS的三方复合物。他们的鼠同源物NCP1，Contactin和Neurofascin 155KDA同工型（NF155）在Axo-Glial SJS上也形成了复合物。我们对果蝇神经毒素和小鼠NCP1突变体的表型分析表明，两个突变体都缺乏SJ。 在此应用中，我们建议在果蝇和小鼠中使用遗传，细胞生物学，分子和生化方法来解决以下问题： （1）在蝇中胚胎发育过程中轴向胶质的何时会形成； Axo-Glial SJ的形成是否与NRX，CON和NRG的表达相一致？ NRX，续和NRG突变体中是否不存在Axo-Glial SJS？ （2）NRX，续和NRG与蝇中SJ的形成的关系是什么？ NRX，续和NRG足以形成SJS吗？ （3）NRG小鼠同源物（NF155）的功能表型的损失是什么？ NF155在形成偏阳形轴胶的SJ中起什么作用？ 我们的研究将为轴突互动的机制提供新的见解。将来，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。