Molecular Characterization of Axon-Glial Interactions

轴突和神经胶质细胞之间的分子相互作用构成了一个巨大的兴趣领域。 许多疾病通过改变结构和功能关系而产生使人衰弱的作用 轴突和神经胶质细胞之间，这反过来又影响动作电位的传播，甚至神经元 生存在脊椎动物有髓轴突中，一种结构特化，即轴-胶质分隔连接， (SJ)在髓鞘环和轴突表面之间的旁阳极处形成。轴神经胶质SJS是 其特征在于具有梯状电子致密结构。我们最近的研究表明，轴胶质细胞SJS 也存在于果蝇的神经中。 除了结构上的相似性，令人信服的分子同源性之间观察轴。 果蝇和小鼠的胶质细胞SJS。果蝇蛋白：Neurexin（NRX）、Contactin（CONT） 和神经胶质细胞（NRG）形成定位于轴胶质细胞SJS的三重复合体。他们的鼠 同源物NCP 1、接触蛋白和神经成束蛋白155kDa同种型（NF 155）也在轴- 胶质SJS。我们对果蝇neurexin和小鼠NCP 1突变体的表型分析表明， 两种突变体都缺乏SJS。 在本申请中，我们建议使用遗传学、细胞生物学、分子和生物化学方法， 果蝇和老鼠回答以下问题： (1)在果蝇胚胎发育过程中，轴胶质SJ何时形成？ 形成与NRX、CONT和NRG的表达一致。轴神经胶质细胞是否缺失 nrg，nrg和nrg突变体中的基因吗？ (2)NRX、CONT和NRG与果蝇SJS的形成有什么关系？是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？什么角色 NF 155在结旁轴胶质细胞SJS的形成中起作用吗？ 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，这些研究将促进我们对伴随的功能缺陷的理解。 脱髓鞘疾病

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.