Molecular Characterization of Axon-Glial Interactions

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巨大的兴趣领域。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。在脊椎动物的髓鞘轴突中，在髓鞘环和轴突表面之间的副极形成了一种结构特化，即轴-胶质隔结（axo-glial sepentjunction， SJ）。轴突胶质sj具有阶梯状的电子致密结构。我们最近的研究表明，轴胶质细胞也存在于果蝇神经中。除了结构上的相似性外，在果蝇和小鼠的轴突神经胶质sj之间观察到令人信服的分子同源性。果蝇蛋白：Neurexin (NRX), Contactin （CONT）和Neuroglian （NRG）形成一个定位于轴胶质SJs的三方复合物。它们的小鼠同源物NCP1、contactn和Neurofascin 155kDa异构体（NF155）也在轴胶质SJs处形成复合物。我们对果蝇neurexin和小鼠NCP1突变体的表型分析表明，这两种突变体都缺乏SJs。

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.