Inactivation of the glial fibrillary acidic protein gene, but not that of vimentin, improves neuronal survival and neurite growth by modifying adhesion molecule expression

Intermediate filaments (IFs) are a major component of the cytoskeleton in a strocytes. Their role is far from being completely understood. Immature ast rocytes play a major role in neuronal migration and neuritogenesis, and the ir IFs are mainly composed of vimentin. In mature differentiated astrocytes , vimentin is replaced by the IF protein glial fibrillary acidic protein (G FAP). In response to injury of the CNS in the adult, astrocytes become reac tive, upregulate the expression of GFAP, and reexpress vimentin. These modi fications contribute to the formation of a glial scar that is obstructive t o axonal regeneration. Nevertheless, astrocytes in vitro are considered to be the ideal substratum for the growth of embryonic CNS axons. In the prese nt study, we have examined the potential role of these two major IF protein s in both neuronal survival and neurite growth. For this purpose, we cocult ured wild-type neurons on astrocytes from three types of knock-out (KO) mic e for GFAP or/and vimentin in a neuron-astrocyte coculture model. We show t hat the double KO astrocytes present many features of immaturity and greatl y improve survival and neurite growth of cocultured neurons by increasing c ell-cell contact and secreting diffusible factors. Moreover, our data sugge st that the absence of vimentin is not a key element in the permissivity of the mutant astrocytes. Finally, we show that only the absence of GFAP is a ssociated with an increased expression of some extracellular matrix and adh esion molecules. To conclude, our results suggest that GFAP expression is a ble to modulate key biochemical properties of astrocytes that are implicate d in their permissivity.