A diverse set of proteoglycans, the major component of extracellular matrix is constitutively expressed in developed and adult brain. This is in stark contrast to the fact that most other extracellular matrix components, including fibronectin, laminin, collagens, and tenascin, are not expressed or are only transiently expressed during development in the brain parenchyma. This suggests that proteoglycans may play a major functional role in cell-cell and cell-matrix interactions in the brain. By employing an approach using polyclonal antibodies which recognize multiple proteoglycan core proteins, we have molecularly cloned a novel chondroitin sulfate proteoglycan in the brain (Yamada, H., Watanabe, K., Shimonaka, M., and Yamaguchi, Y. J. Biol. Chem. in press). This proteoglycan, named """"""""brevican"""""""", is a member of the aggrecan/versican family, containing a hyaluronic acid-binding domain in its N-terminus and a lectin-like domain in its C-terminus. Brevican has the smallest core protein among this family of proteoglycans and is one of the most abundant chondroitin sulfate proteoglycans in the postnatal brain. Expression of brevican is highly specific in the brain and increases as the brain develops. In neuron-astrocyte cocultures, strong brevican immunoreactivity is detected at the contact sites between neuronal cell bodies and astrocytes as well as along neurites, suggesting that brevican may play a role in neuron-glia interactions. Several proteins in brain membrane extracts have been shown to specifically bind to a C-terminal fragment of the brevican core protein that contains the lectin-like domain. Among these binding proteins, chondroitin sulfate proteoglycans with core proteins of 170 kDa and 220 kDa appear to be the major brevican- binding proteins in the brain. Thus, the specific aims of this proposal are: 1) to determine the tissue distribution and developmental expression of brevican in the rat nervous system; 2) to characterize brevican-binding proteins; and 3) to determine the role of brevican in neurite outgrowth and neuron-glia interactions. Our long-term objective is to elucidate the role of brevican in the development of the nervous system in vivo. Since proteoglycans have been implicated in the formation of amyloid plaques in Alzheimer's disease, these studies could also contribute to understanding the mechanism of amyloid deposition and the progression of neurodegenerative processes.
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