The growth-associated protein gap-43 appears in dorsal root ganglion cells and in the dorsal horn of the rat spinal cord following peripheral nerve injury

Woolf, Clifford J.; Reynolds, M. L.; Molander, Carl; O’Brien, Claire; Lindsay, Ronald M.; Benowitz, Larry I.

doi:10.1016/0306-4522(90)90155-w

Cited by 313 publications

(134 citation statements)

References 41 publications

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“…Indeed, injury-mediated repression of mRNA encoding neurofilament-L occurs via elements in the 3Ј untranslated region (Schwartz et al, 1995). Both 5Ј flanking sequence and a minimum of 11 kb of intron 1 are needed for accurate cell type-specific regulation and activation after injury of the GAP-43 gene ( Vanselow et al, 1994), which, like peripherin, shows an injurymediated increase in mRNA (Woolf et al, 1990). The precise location of the GAP-43 injury-response elements, however, remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Intron 1 Is Required for Cell Type-Specific, But Not Injury-Responsive, Peripherin Gene Expression

et al. 2002

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The "primitive" neurons of the peripheral nervous system (PNS) have the remarkable ability to regenerate new fibers. This regenerative process requires a sequence of gene activation and repression that is poorly understood. One gene that is almost exclusively expressed in neurons of the PNS and is activated after nerve injury is the peripherin intermediate filament gene, but little is known about the genomic elements that control either its restricted expression or its response to nerve injury in adult mice. Previous studies suggested that both 5Ј flanking sequence and intragenic regions were required for cell typespecific and injury-specific expression. To determine which intragenic regions were critical, mice were generated that expressed peripherin transgenes lacking different introns. Analyses of these mice revealed that deletion of introns 2-8 had no effect on either the cell type-specific or injury-specific expression of the peripherin gene; however, the remaining intron, intron 1, differentially bound Sp1 transcription-related proteins/ protein complexes in extracts from peripherin-expressing and nonexpressing tissues. Furthermore, a transgene that lacked intron 1 was not expressed in many neurons that contain endogenous peripherin but was activated after injury. Thus, accurate cell type-specific peripherin gene expression in the PNS depends on elements within intron 1, but other sequences, most likely in the 5Јflanking region, are required for activating the peripherin gene in response to nerve injury.

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Section: Discussionmentioning

confidence: 99%

Intron 1 Is Required for Cell Type-Specific, But Not Injury-Responsive, Peripherin Gene Expression

et al. 2002

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“…Peripheral neuropathy has been reported to induce expression of growth-associated protein-43 (GAP-43) in two vital locations of the nociceptive network: the dorsal root ganglion and the superficial dorsal horn of the spinal cord (Coggeshall et al, 1991;Woolf et al, 1990). GAP-43 is traditionally regarded as a marker of sprouting fibers, but it can also be indicative of regeneration or neuronal plasticity (Oestreicher et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Thus increased GAP-43 expression may be an early indicator of structural changes within the nociceptive network, which alters the processing of noxious and innocuous information following nerve injury. Although this pathological process has been claimed to be particularly relevant to mechanical pain hypersensitivity Latremoliere and Woolf, 2009;Woolf et al, 1990), a limited understanding of the regulators of GAP-43 expression explains why it is still unknown whether such structural changes play a role in neuropathy-induced mechanical pain hypersensitivity.…”

Section: Introductionmentioning

confidence: 99%

Neuropathy-Induced Spinal GAP-43 Expression Is Not a Main Player in the Onset of Mechanical Pain Hypersensitivity

Jaken

Gorp

Joosten

et al. 2011

Journal of Neurotrauma

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Structural plasticity within the spinal nociceptive network may be fundamental to the chronic nature of neuropathic pain. In the present study, the spatiotemporal expression of growth-associated protein-43 (GAP-43), a protein which has been traditionally implicated in nerve fiber growth and sprouting, was investigated in relation to mechanical pain hypersensitivity. An L5 spinal nerve transection model was validated by the presence of mechanical pain hypersensitivity and an increase in the early neuronal activation marker cFos within the superficial spinal dorsal horn upon innocuous hindpaw stimulation. Spinal GAP-43 was found to be upregulated in the superficial L5 dorsal horn from 5 up to 10 days after injury. GAP-43 was co-localized with calcitoningene related peptide (CGRP), but not vesicular glutamate transporter-1 (VGLUT-1), IB4, or protein kinase-c (PKC-c), suggesting the regulation of GAP-43 in peptidergic nociceptive afferents. These GAP-43/CGRP fibers may be indicative of sprouting peptidergic fibers. Fiber sprouting largely depends on growth factors, which are typically associated with neuro-inflammatory processes. The putative role of neuropathy-induced GAP-43 expression in the development of mechanical pain hypersensitivity was investigated using the immune modulator propentofylline. Propentofylline treatment strongly attenuated the development of mechanical pain hypersensitivity and glial responses to nerve injury as measured by microglial and astroglial markers, but did not affect neuropathy-induced levels of spinal GAP-43 or GAP-43 regulation in CGRP fibers. We conclude that nerve injury induces structural plasticity in fibers expressing CGRP, which is regarded as a main player in central sensitization. Our data do not, however, support a major role of these structural changes in the onset of mechanical pain hypersensitivity.

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“…The second is the induction of a regenerative capacity in the injured neurons (Skene, 1989), presumably because of upregulation of developmentally regulated growth-related proteins such as GAP-43 (Chong et al, 1992). GAP-43 is transported to central terminals of injured sensory neurons in lamina II (Woolf et al, 1990), which is the region that contains novel transganglionic B-HRP labeling (Woolf et al, 1995). Therefore, peripheral nerve injury may induce both the molecular machinery necessary for growth and provide a denervated area for the sprouts to grow into.…”

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confidence: 99%

Collateral Sprouting of Uninjured Primary Afferent A-Fibers into the Superficial Dorsal Horn of the Adult Rat Spinal Cord after Topical Capsaicin Treatment to the Sciatic Nerve

et al. 1996

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That terminals of uninjured primary sensory neurons terminating in the dorsal horn of the spinal cord can collaterally sprout was first suggested by Liu and Chambers (1958), but this has since been disputed. Recently, horseradish peroxidase conjugated to the B subunit of cholera toxin (B-HRP) and intracellular HRP injections have shown that sciatic nerve section or crush produces a long-lasting rearrangement in the organization of primary afferent central terminals, with A-fibers sprouting into lamina II, a region that normally receives only C-fiber input (Woolf et al., 1992). The mechanism of this A-fiber sprouting has been thought to involve injury-induced C-fiber transganglionic degeneration combined with myelinated A-fibers being conditioned into a regenerative growth state.In this study, we ask whether C-fiber degeneration and A-fiber conditioning are both necessary for the sprouting of A-fibers into lamina II. Local application of the C-fiber-specific neurotoxin capsaicin to the sciatic nerve has previously been shown to result in C-fiber damage and degenerative atrophy in lamina II. We have used B-HRP to transganglionically label A-fiber central terminals and have shown that 2 weeks after topical capsaicin treatment to the sciatic nerve, the pattern of B-HRP staining in the dorsal horn is indistinguishable from that seen after axotomy, with lamina II displaying novel staining in the identical region containing capsaicin-treated C-fiber central terminals.These results suggest that after C-fiber injury,uninjuredA-fiber central terminals can collaterally sprout into lamina II of the dorsal horn. This phenomenon may help to explain the pain associated with C-fiber neuropathy.

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The growth-associated protein gap-43 appears in dorsal root ganglion cells and in the dorsal horn of the rat spinal cord following peripheral nerve injury

Cited by 313 publications

References 41 publications

Intron 1 Is Required for Cell Type-Specific, But Not Injury-Responsive, Peripherin Gene Expression

Intron 1 Is Required for Cell Type-Specific, But Not Injury-Responsive, Peripherin Gene Expression

Neuropathy-Induced Spinal GAP-43 Expression Is Not a Main Player in the Onset of Mechanical Pain Hypersensitivity

Collateral Sprouting of Uninjured Primary Afferent A-Fibers into the Superficial Dorsal Horn of the Adult Rat Spinal Cord after Topical Capsaicin Treatment to the Sciatic Nerve

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