Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration.

The regenerative capacity of the CNS is extremely limited. The reason for this is unclear, but glial cell involvement has been suspected, and oligodendrocytes have been implicated as inhibitors of neuroregeneration (Chen et al., 2000, GrandPre et al., 2000; Fournier et al., 2001). The role of astrocytes in this process was proposed but remains incompletely understood (Silver and Miller, 2004). Astrocyte activation (reactive gliosis) accompanies neurotrauma, stroke, neurodegenerative diseases, or tumors. Two prominent hallmarks of reactive gliosis are hypertrophy of astrocytic processes and upregulation of intermediate filaments. Using the entorhinal cortex lesion model in mice, we found that reactive astrocytes devoid of the intermediate filament proteins glial fibrillary acidic protein and vimentin (GFAP-/-Vim-/-), and consequently lacking intermediate filaments (Colucci-Guyon et al., 1994; Pekny et al., 1995; Eliasson et al., 1999), showed only a limited hypertrophy of cell processes. Instead, many processes were shorter and not straight, albeit the volume of neuropil reached by a single astrocyte was the same as in wild-type mice. This was accompanied by remarkable synaptic regeneration in the hippocampus. On a molecular level, GFAP-/-Vim-/- reactive astrocytes could not upregulate endothelin B receptors, suggesting that the upregulation is intermediate filament dependent. These findings show a novel role for intermediate filaments in astrocytes and implicate reactive astrocytes as potent inhibitors of neuroregeneration.

Loss of GFAP expression in high-grade astrocytomas does not contribute to tumor development or progression.

In astrocytic neoplasms, the number of cells expressing glial fibrillary acidic protein (GFAP) is inversely proportional to the extent of anaplasia. The loss of GFAP expression, the principal marker of astroglial cells, in these tumors has been proposed to constitute a step in their development and progression. To test this hypothesis, we crossed p53-negative (p53(-/-)) mice, which frequently develop astrocytomas after intrauterine exposure to ethylnitrosourea, with GFAP-negative (GFAP(-/-)) mice or GFAP(+/+) controls. Brain tumors of glial origin were found in 12 of 35 GFAP(+/+) p53(-/-) mice (34%) and in 11 of 27 GFAP(-/-) p53(-/-) mice (41%). The two groups did not differ in the age at which tumors were detected or in tumor histology or progression. Thus, the loss of GFAP expression frequently seen in high-grade astrocytomas does not constitute a step in tumor development. Rather, it may represent the undifferentiated state of these cells.