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.
Wilhelmsson
Ulrika
U
Department of Medical Biochemistry, Sahlgrenska Academy at Göteborg University, SE-405 30 Göteborg, Sweden.
Li
Lizhen
L
Pekna
Marcela
M
Berthold
Claes-Henric
CH
Blom
Sofia
S
Eliasson
Camilla
C
Renner
Oliver
O
Bushong
Eric
E
Ellisman
Mark
M
Morgan
Todd E
TE
Pekny
Milos
M
D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000648:ultrastructure; D018728:Entorhinal Cortex / Q000293:injuries; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism*; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure*; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000502:physiology*; D044023:Receptor, Endothelin B / Q000378:metabolism; D015854:Up-Regulation; D014746:Vimentin / Q000378:metabolism*
D005904:Glial Fibrillary Acidic Protein; D044023:Receptor, Endothelin B; D014746:Vimentin; D005974:Glutamate-Ammonia Ligase