THE BRAIN CHONDROITIN SULFATE PROTEOGLYCAN BREVICAN ASSOCIATES WITH ASTROCYTES ENSHEATHING CEREBELLAR GLOMERULI AND INHIBITS NEURITE OUTGROWTH FROM GRANULE NEURONS

Brevican is a nervous system-specific chondroitin sulfate proteoglycan that belongs to the aggrecan family and is one of the most abundant c hondroitin sulfate proteoglycans in adult brain. To gain insights into the role of brevican in brain development, we investigated its spatio temporal expression, cell surface binding, and effects on neurite outg rowth, using rat cerebellar cortex as a model system. Immunoreactivity of brevican occurs predominantly in the protoplasmic islet in the int ernal granular layer after the third postnatal week, Immunoelectron mi croscopy revealed that brevican is localized in close association with the surface of astrocytes that form neuroglial sheaths of cerebellar glomeruli where incoming messy fibers interact with dendrites and axon s from resident neurons. In situ hybridization showed that brevican is synthesized by these astrocytes themselves. In primary cultures of ce rebellar astrocytes, brevican is detected on the surface of these cell s. Binding assays with exogenously added brevican revealed that primar y astrocytes and several immortalized neural cell lines have cell surf ace binding sites for brevican core protein. These cell surface brevic an binding sites recognize the C-terminal portion of the core protein and are independent of cell surface hyaluronan. These results indicate that brevican is synthesized by astrocytes and retained on their surf ace by an interaction involving its core protein. Purified brevican in hibits neurite outgrowth from cerebellar granule neurons in vitro, an activity that requires chondroitin sulfate chains. We suggest that bre vican presented on the surface of neuroglial sheaths may be controllin g the infiltration of axons and dendrites into maturing glomeruli.