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

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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.