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极具吸引力的领域。 许多疾病通过改变结构和功能关系而产生衰弱效应。 在轴突和神经胶质细胞之间，这反过来影响动作电位的传播，甚至神经元 生死存亡。在脊椎动物中，有髓轴突是一种结构特化，轴突-神经胶质间隔连接 (Sj)，在髓鞘环和轴突表面之间的副阳极处形成。轴突胶质细胞SJS是 以梯形电子密度结构为特征的。我们最近的研究表明，轴突胶质细胞的SJS 也存在于果蝇的神经中。 除了结构上的相似性外，还观察到了两个轴-之间令人信服的分子同源性。 苍蝇和小鼠的神经胶质SJS。果蝇蛋白质：Neuresin(NRX)、Contact(CONT) 和神经胶质细胞(NRG)形成一个定位于轴突-胶质细胞SJS的三部分复合体。他们的小鼠 NCP1、Contactin和NeuroFasin 155 kDa异构体(NF155)的同源物也在轴突形成复合体。 神经胶质SJS。我们对果蝇和小鼠NCP1突变体的表型分析表明， 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、分子和生化方法来 果蝇和老鼠要解决以下问题： (1)果蝇胚胎发育过程中轴突何时形成，轴突是否形成？ 其形成与NRX、CONT、NRG？的表达一致。轴突胶质细胞SJS缺失吗？ 在NRX、CONT和NRG突变体中？ (2)NRX、CONT、NRG与果蝇SJS的形成有何关系？是NRX， CONT和NRG足以形成SJS吗？ (3)NRG(NF155)小鼠同源基因的功能缺失表型是什么？什么角色 NF155是否参与结旁轴索-神经胶质SJS的形成？ 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……里面 在未来，这些研究将促进我们对伴随而来的功能缺陷的理解 脱髓鞘障碍。

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.