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James T. Rutka, Masaji Murakami, Peter B. Dirks, Sherri Lynn Hubbard, Laurence E. Becker, Kozo Fukuyama, Shin Jung and Kazuhito Matsuzawa

In the adult human brain, normal astrocytes constitute nearly 40% of the total central nervous system (CNS) cell population and may assume a star-shaped configuration resembling epithelial cells insofar as the astrocytes remain intimately associated, through their cytoplasmic extensions, with the basement membrane of the capillary endothelial cells and the basal lamina of the glial limitans externa. Although their exact function remains unknown, in the past, astrocytes were thought to subserve an important supportive role for neurons, providing a favorable ionic environment, modulating extracellular levels of neurotransmitters, and serving as spacers that organize neurons. In immunohistochemical preparations, normal, reactive, and neoplastic astrocytes may be positively identified and distinguished from other CNS cell types by the expression of the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). This GFAP is a 50-kD intracytoplasmic filamentous protein that constitutes a portion of, and is specific for, the cytoskeleton of the astrocyte. This protein has proved to be the most specific marker for cells of astrocytic origin under normal and pathological conditions. Interestingly, with increasing astrocytic malignancy, there is progressive loss of GFAP production. As the human gene for GFAP has now been cloned and sequenced, this review begins with a summary of the molecular biology of GFAP including the proven utility of the GFAP promoter in targeting genes of interest to the CNS in transgenic animals. Based on the data provided the authors argue cogently for an expanded role of GFAP in complex cellular events such as cytoskeletal reorganization, maintenance of myelination, cell adhesion, and signaling pathways. As such, GFAP may not represent a mere mechanical integrator of cellular space, as has been previously thought. Rather, GFAP may provide docking sites for important kinases that recognize key cellular substrates that enable GFAP to form a dynamic continuum with microfilaments, integrin receptors, and the extracellular matrix.

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James T. Rutka, Masaji Murakami, Peter B. Dirks, Sherri Lynn Hubbard, Laurence E. Becker, Kozo Fukuyama, Shin Jung, Atsushi Tsugu and Kazuhito Matsuzawa

cells outside the CNS, such as nonmyelinating Schwann cells, the epithelium of the lens, the epithelial cells of salivary glands and their neoplasms, and neoplastic cells of mullerian origin. 95 Molecular Biology of GFAP The amino acid sequence of human GFAP has been deduced from the nucleotide sequence of complementary (c)DNA clones encoding this protein. 9, 12, 90 Mouse and human GFAP genomic genes have also been cloned and sequenced. 3, 63, 80 There is high homology among rat, mouse, and human GFAP in the coding regions of the gene, but less so in the 3

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Paul C. Park, Michael D. Taylor, Todd G. Mainprize, Laurence E. Becker, Michael Ho, Wieslaw T. Dura, Jeremy Squire and James T. Rutka

Object. Although medulloblastoma is the most common malignant brain tumor found in children, little is known about its molecular pathogenesis. The authors have attempted to compare patterns of gene expression in medulloblastoma samples with those in the healthy cerebellum.

Methods. The authors used complementary (c)DNA microarray analysis to compare the expression of genes in samples of medulloblastoma and normal cerebellum. The expression levels of a subset of genes were then verified by immunohistochemical analysis. Six genes were identified that were expressed at a much higher level in at least five of six medulloblastomas: ezrin, cyclin D2, high mobility group protein 2, MAPRE1, histone deacetylase 2, and ornithine decarboxylase 1. A number of potentially important genes whose expression was much lower in medulloblastomas than in control cerebellum were also identified: tenascin R, TRK-B, FGF receptor, and death receptor 3. The expression levels of a subset of the identified genes were confirmed by immunohistochemical analysis, which was performed on fetal cerebellum and medulloblastoma samples.

Conclusions. The authors demonstrate that cDNA microarray analysis is an effective method of increasing understanding of the molecular biology of medulloblastomas found in children. A comparison between gene expression patterns in medulloblastoma and those observed in healthy cerebellum may provide clues as to the origin of these tumors and may lead to the identification of new genes or pathways to be targeted for future therapies.