Astrocytes comprise a large proportion of CNS cells. They are thought to originate among the neuroectodermal cells of germinal zones. While immature cells form few cellular contacts, astrocytes form many close interactions with other cells and with extracellular elements. Astrocytic differentiation thus must involve major changes in the cell surface. Little is known of the molecular characteristics of astrocyte membranes, however. Astrocytes also comprise the major cellular component of glial scars, a pathological result common to a great many neurological disorders, including demyelinating diseases, trauma, stroke and neurodegenerative diseases. In scarring, astrocytes accumulate large amounts of the intermediate filament protein, glial fibrillary acidic protein (GFAP). We propose a series of studies to examine several morphological and biochemical characteristics of astrocytes during glial differentiation and during gliosis. We have recently found that GD3 ganglioside is a major and characteristic cell surface component of immature CNS cells, and of astrocytes in glial scars. Because of the restricted localization of this molecule to immature cells, we will use an anti-GD3 antibody to select for immature cells from newborn rat CNS. We are developing a cell culture system in chemically-defined, serum-free medium to allow proliferation of these cells. Our preliminary studies show this is possible and, furthermore, that we will be able to induce astrocytic differentiation by alterations in growth medium. We propose to study glial differentiation in detail, examining possible stimuli that induce and maintain the process. We will concentrate on intermediate filament expression and characterization of cell surface molecules. We will also continue our current studies on cytoskeletal organization and metabolism in astrocytes, in which we have found experimental means of modulating GFAP expression. One of these means appears to be cAMP-dependent. Finally, we will examine molecular changes in astrocytes during gliosis, in particular changes in GFAP expression and surface molecules. We will use in vivo systems of traumatic lesions, and murine mutants which display gliosis.
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