The role of heparansulfate proteoglycan agrin at the retina - basal lamina interface in the developing CNS

聚集蛋白是一种硫酸乙酰肝素蛋白聚糖，广泛表达于大多数器官。然而，聚集蛋白的功能最好在神经肌肉接头处理解，在那里它负责大多数（如果不是所有的话）突触后特化的形成、维持和再生，包括含有乙酰胆碱受体、乙酰胆碱酯酶和其他分子的聚集体。聚集蛋白还调节神经肌肉接头处的突触特异性基因表达。选择性剪接产生几种聚集蛋白同种型，它们的分布和生物活性不同。所有的聚集蛋白异构体在整个发育中的中枢神经系统的神经元和神经胶质细胞中表达，但聚集蛋白在中枢神经系统中的功能是未知的。本申请的主要目的是分析聚集蛋白在特定CNS基底层（视网膜内界膜）中的作用，以鉴定参与聚集蛋白与基底层体内相互作用的聚集蛋白的结构域，以鉴定聚集蛋白在相邻视网膜细胞中的结合配偶体，并研究基底层结合的聚集蛋白对直接贴壁的神经胶质细胞膜中分子分布的可能影响。这些研究将有希望导致更好地了解基底层相关聚集蛋白在CNS发展过程中的作用，以及细胞外基质在CNS中的作用。

Agrin is a heparansulfate proteoglycan which is widely expressed throughout most organs. Agrin´s function, however, is best understood at the neuromuscular junction where it is responsible for the formation, maintenance and regeneration of most if not all postsynaptic specializations, including aggregates containing acetylcholine receptors, acetylcholine esterase and other molecules. Agrin also regulates synapse-specific gene expression at the neuromuscular junction. Alternative splicing generates several agrin isoforms which differ in their distribution and biological activity. All agrin isoforms are expressed throughout the developing CNS by neurons and glial cells, but the function of agrin in the CNS is unknown. The main goal of this application is to analyze the role of agrin in a particular CNS basal lamina, the retinal inner limiting membrane, to identify the domains of agrin involved in the interaction of agrin with a basal lamina in vivo, to identify binding partners of agrin in the adjacent retinal cells, and to investigate a possible influence of basal lamina-bound agrin on the distribution of molecules in the directly-apposed glial cell membrane. These studies will hopefully lead to a better understanding of the role of basal lamina-associated agrin during CNS-development and of the role of the extracellular matrix in the CNS in general.