ASTROCYTOSIS AND AXONAL PROLIFERATION IN THE HIPPOCAMPUS OF S100B TRANSGENIC MICE

S100 beta is a calcium-binding protein that is expressed at high level s in brain primarily by astrocytes. Addition of the disulfide-bonded d imeric form of S100 beta to primary neuronal and glial cultures and es tablished cell lines induces axonal extension and alterations in astro cyte proliferation and phenotype, but evidence that S100 beta exerts t he same effects in vivo has not been presented. An 8.9-kb murine S100b genomic clone was used to produce two lines of transgenic mice in whi ch S100 beta RNA is increased in a dose-related manner to 2-fold and 7 -fold above normal. These lines show concomitant increased S100 beta p rotein throughout the brain. Expression in both lines is cell type- an d tissue-appropriate, and expression levels are correlated with the tr ansgene copy number, demonstrating that sequences necessary for normal regulation of the gene are included within the cloned segment. In the hippocampus of adult transgenic mice, Western blotting detects elevat ed levels of glial fibrillary acidic protein and several markers of ax onal sprouting, including neurofilament L, phosphorylated epitopes of neurofilament H and M, and beta-tubulin. Immunocytochemistry demonstra tes alterations in astrocyte morphology and axonal sprouting, especial ly in the dentate gyrus. Thus, both astrocytosis and neurite prolifera tion occur in transgenic mice expressing elevated levels of S100P beta These transgenic mice provide a useful model for studies of the role of S100 beta in glial-neuronal interactions in normal development and function of the brain and for analyzing the significance of elevated l evels of S100 beta in Down syndrome and Alzheimer disease.