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The Journal of Neuroscience, May 26, 2004, 24(21):5016-5021; doi:10.1523/JNEUROSCI.0820-04.2004
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Development/Plasticity/Repair
Absence of Glial Fibrillary Acidic Protein and Vimentin Prevents Hypertrophy of Astrocytic Processes and Improves Post-Traumatic Regeneration
Ulrika Wilhelmsson,1 Lizhen Li,1 Marcela Pekna,1 Claes-Henric Berthold,2 Sofia Blom,1 Camilla Eliasson,1 Oliver Renner,5 Eric Bushong,4 Mark Ellisman,4 Todd E. Morgan,3 andMilos Pekny1 1Department of Medical Biochemistry and 2Department of Anatomy and Cell Biology, Sahlgrenska Academy at Göteborg University, SE-405 30 Göteborg, Sweden, 3Andrus Gerontology Center, University of Southern California, Los Angeles, California 90089-0191, 4National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, California 92093-0608, and 5Spanish National Cancer Centre, E-28029 Madrid, Spain
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.
Key words: GFAP; vimentin; intermediate filaments; astrocytes; regeneration; hippocampus; endothelin B receptor
Received Sep 18, 2003; revised April 8, 2004; accepted April 14, 2004.
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