Dystrophin-related protein/utrophin is a large, cytoskeletal protein that shares significant sequence similarity with dystrophin. Dystrophin-related protein is known to be enriched where cell-extracellular matrix contacts are well defined; however, the mechanism of dystrophin-related protein enrichment and its functional role(s) at these sites are yet to be defined. Here, we demonstrate that dystrophin-related protein is concentrated in patches of astrocyte membrane in apposition with the extracellular matrix and that the distribution of dystrophin-related protein is temporally modulated by the extracellular matrix constituent laminin. Furthermore, we demonstrate the existence of a specific biochemical association between dystrophin-related protein and laminin in astrocytes. In these astrocytes, the depletion of dystrophin-related protein by the use of antisense dystrophin-related protein oligonucleotides causes marked reduction in the formation of functional substratum-membrane attachments. Taken together, these data suggest that dystrophin-related protein may function in the generation and maintenance of regional substratum-associated membrane specializations, such as those found at the blood-brain barrier.

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