Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes

Menet, Véronique; Prieto, M.; Privat, Alain; Ribotta, Minerva Giménez y

doi:10.1073/pnas.1533187100

Cited by 285 publications

(211 citation statements)

References 38 publications

(44 reference statements)

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“…Consequent to this, the reactive astrocytes are able to release inhibitory extracellular matrix molecules known as CSPG, which forms the major component of the glial scar after SCI. Moreover it has been found that mice that are deficient in the GFAP and vimentin genes show significantly improved axonal plasticity and functional recovery after spinal cord injury (69). Our results demonstrated that expression of GFAP at the transcriptional and translational levels was elevated after SCI.…”

Section: Discussionsupporting

confidence: 61%

Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

Tsai¹,

Shen²,

Kuo

et al. 2008

Molecular & Cellular Proteomics

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Acidic fibroblast growth factor (aFGF; also known as FGF-1) is a potent neurotrophic factor that affects neuronal survival in the injured spinal cord. However, the pathological changes that occur with spinal cord injury (SCI) and the attribution to aFGF of a neuroprotective effect during SCI are still elusive. In this study, we demonstrated that rat SCI, when treated with aFGF, showed significant functional recovery as indicated by the Basso, Beattie, and Bresnahan locomotor rating scale and the combined behavior score (p < 0.01-0.001). Furthermore proteomics and bioinformatics approaches were adapted to investigate changes in the global protein profile of the damaged spinal cord tissue when experimental rats were treated either with or without aFGF at 24 h after injury. We found that 51 protein spots, resolvable by two-dimensional PAGE, had significant differential expression. Using hierarchical clustering analysis, these proteins were categorized into five major expression patterns. Noticeably proteins involved in the process of secondary injury, such as astrocyte activation (glial fibrillary acidic protein), inflammation (S100B), and scar formation (keratan sulfate proteoglycan lumican), which lead to the blocking of injured spinal cord regeneration, were down-regulated in the contusive spinal cord after treatment with aFGF. We propose that aFGF might initiate a series of biological processes to prevent or attenuate secondary injury and that this, Spinal cord injury (SCI)1 is a costly disease as well as the most frequent cause of mortality and morbidity in every medical care system around the world (1, 2). Traumatic axonal injury is a primary sequela of contusive SCI and is characterized by axonal swelling and disconnection of the ascending sensory and descending motor tracts (3). Contusive SCI seems to initiate a complicated cascade of pathophysiological changes, a process called secondary injury, including fiber deformation, increased vascular permeability, local ischemia, intraneuronal edema, and local demyelination. Moreover traumatic axonal injury typically involves a disruption of the axonal membrane, and this results in up-regulation of the entry of calcium, the influx of which initiates calpain activation (4, 5) and mitochondrial injury/swelling (6), resulting in cytochrome c release and caspase activation (7). Simultaneously the proliferation and hypertrophy of astrocytes around the injury site are characterized by increased immunoreactivity to glial fibrillary acidic proteins (GFAPs) (8).Although many studies have focused on revealing the pathophysiology of SCI, the exact molecular mechanisms and the biochemical pathways that mediate secondary injury remain sketchy (9). Spinal cord injury often causes permanent neurological deficits mostly because the injured neurons lack regenerative ability, and the series of destructive processes that follow SCI results in a second wave of cell death and spreading tissue loss (10). Therefore, studies of the stimulaFrom the ‡Institute

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Section: Discussionsupporting

confidence: 61%

Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

Tsai¹,

Shen²,

Kuo

et al. 2008

Molecular & Cellular Proteomics

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“…The pharmacological total knock-out of soluble GFAP and vimentin to emulate the combined genetic deficiency of both IFs (Vim GFAP dKO) despite the encouraging results of increased neural regeneration and improvement of CNS functions in Vim GFAP dKO mice (15,52) may come also with some FIGURE 8. WFA differentially regulates cyclin D3 and p27…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, Vim GFAP dKO mice subjected to spinal cord or brain injury recover favorably with improvement of glial scars (14). In fact, the complete absence of type III IFs in Vim GFAP dKO mice helps promote axonal regeneration and regain ambulatory function after spinal cord injury (15). These Vim GFAP dKO mice are also protected from retinal degeneration after experimental retinal detachment (16) and integration of transplanted cells and the extension of neurites in the host retinas of Vim GFAP dKO mice is favored compared with WT mice (17).…”

Section: Gliosis Is a Biological Process That Occurs During Injury Rementioning

confidence: 99%

Withaferin A Targets Intermediate Filaments Glial Fibrillary Acidic Protein and Vimentin in a Model of Retinal Gliosis

Bargagna‐Mohan

Paranthan

Hamza

et al. 2010

Journal of Biological Chemistry

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Gliosis is a biological process that occurs during injury repair in the central nervous system and is characterized by the overexpression of the intermediate filaments (IFs) glial fibrillary acidic protein (GFAP) and vimentin. A common thread in manyThe overexpression of glial fibrillary acidic protein (GFAP) 2 with vimentin is a hallmark of reactive gliosis in the central nervous system (CNS) (1, 2). These intermediate filaments (IFs) are expressed by reactive astrocytes and macro-and microglia during traumatic and inflammatory injury and in a range of CNS degenerative diseases (2). In fact, an enigma of major retinal diseases, including age-related macular degeneration, glaucoma, diabetic retinopathy, and retinopathy of prematurity, is retinal gliosis, for which there is no available clinical treatment (3-5).Important fundamental insights on the structural and mechanical functions of IFs (6, 7) have now been validated in mouse lines deficient in type III IFs (2). These studies have illuminated that, whereas overexpression of vimentin and GFAP during CNS stress response and injury repair contributes to scar formation (8), their deficiency can be protective of tissue functions in certain contexts. For instance, pathogenic angiogenesis is impaired in vimentin-deficient (Vim KO) mice due to the decreased ability of newly formed blood vessels to cross the retinal inner limiting membrane in the model of hypoxia-induced retinal neovascularization (9). Interestingly, that study also identified in vimentin and GFAP double deficient (Vim GFAP dKO) mice, and to a lesser extent in Vim KO mice, that the retinal ganglion layer is highly sensitive to mechanical stress, which was not observed in GFAP KO mice. Pathological neovascularization was also reduced in Vim KO mice in the corneal alkali injury model (10) and delayed vascularization in skin injury model (11), which is attributed to defective vascular endothelial cell integrity (12), because vimentin is the sole type III IF expressed in endothelial cells (13). On the other hand, Vim GFAP dKO mice subjected to spinal cord or brain injury recover favorably with improvement of glial scars (14). In fact, the complete absence of type III IFs in Vim GFAP dKO mice helps promote axonal regeneration and regain ambulatory function after spinal cord injury (15). These Vim GFAP dKO

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“…Extensive glial scarring, seen in MMP-2 null mice, should also be considered in this context. Indeed, mice deficient in both GFAP and vimentin, or with selective ablation of reactive astrocytes, show enhanced axonal sprouting and better functional recovery after injury as a result of reduced reactive astrogliosis (Bush et al, 1999;Pekny et al, 1999;Menet et al, 2003).…”

Section: Axonal Plasticity Tissue Sparing and Mmpsmentioning

confidence: 99%

Matrix Metalloproteinase-2 Facilitates Wound Healing Events That Promote Functional Recovery after Spinal Cord Injury

Hsu¹,

McKeon²,

Goussev³

et al. 2006

J. Neurosci.

205

184

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Matrix metalloproteinases (MMPs) are proteolytic enzymes that are involved in both injury and repair mechanisms in the CNS. Pharmacological blockade of MMPs, limited to the first several days after spinal cord injury, improves locomotor recovery. This beneficial response is, however, lost when treatment is extended beyond the acutely injured cord to include wound healing and tissue remodeling. This suggests that some MMPs play a beneficial role in wound healing. To test this hypothesis, we investigated the role of MMP-2, which is actively expressed during wound healing, in white matter sparing and axonal plasticity, the formation of a glial scar, and locomotor recovery after spinal cord injury. MMP-2 increased between 7 and 14 d after injury, where it was immunolocalized in reactive astrocytes bordering the lesion epicenter. There was reduced white matter sparing and fewer serotonergic fibers, caudal to the lesion in injured MMP-2 null animals. MMP-2 deficiency also resulted in increased immunoreactivity to chondroitin sulfate proteoglycans and a more extensive astrocytic scar. Most importantly, locomotion in an open field, performance on a rotarod, and grid walking were significantly impaired in injured MMP-2 null mice. Our findings suggest that MMP-2 promotes functional recovery after injury by regulating the formation of a glial scar and white matter sparing and/or axonal plasticity. Thus, strategies exploiting MMPs as therapeutic targets must balance these beneficial effects during wound healing with their adverse interactions in the acutely injured spinal cord.

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Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes

Cited by 285 publications

References 38 publications

Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

Withaferin A Targets Intermediate Filaments Glial Fibrillary Acidic Protein and Vimentin in a Model of Retinal Gliosis

Matrix Metalloproteinase-2 Facilitates Wound Healing Events That Promote Functional Recovery after Spinal Cord Injury

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