Persistent restoration of sensory function by immediate or delayed systemic artemin after dorsal root injury

Wang, Ruizhong; King, Tamara; Ossipov, Michael H.; Rossomando, Anthony; Vanderah, Todd W.; Harvey, Pamela A.; Cariani, Peter; Frank, Eric; Sah, Dinah W.Y.; Porreca, Frank

doi:10.1038/nn2069

Cited by 90 publications

(112 citation statements)

References 46 publications

Supporting

Mentioning

102

Contrasting

Unclassified

Order By: Relevance

“…Because unmyelinated axons lack NgR expression, they might be less responsive to a blockade of myelin-associated inhibition than myelinated axons (11). In contrast, CGRP expression recovers following ART treatment, consistent with expression of the specific ART receptor, GFRα3, on unmyelinated neurons (9,12,13), suggesting that these afferents are regenerating (Fig. 3E).…”

Section: Resultsmentioning

confidence: 78%

“…1A). After cervical DR crush, sensory projections within the cord degenerated, and no projections were labeled by CTB in the dorsal horn, confirming the complete interruption of this pathway into the spinal cord (8,9).…”

Section: Resultsmentioning

confidence: 78%

“…In contrast, systemic ART treatments promoted robust regeneration of CTB-labeled afferents throughout the dorsal horn except within the upper laminae, thereby restoring the normal pattern of projections (Fig. 1C) (9).…”

Section: Resultsmentioning

confidence: 96%

“…Application of two agents-a soluble Nogo receptor peptide (sNgR), which binds to Nogo receptor ligands and abrogates their inhibitory effect (7), and artemin (ART), a member of the glial-derived neurotrophic factor familypromote robust regeneration of sensory axons after DR crush (8,9). The specificity of projections of specific classes of sensory axons to appropriate target areas within the spinal cord has not yet been investigated, however.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Topographically specific regeneration of sensory axons in the spinal cord

Harvey

Gong

Rossomando

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Artemin, a member of the glial-derived neurotrophic factor family, promotes robust regeneration of sensory axons after dorsal root crush. We report here that several classes of sensory axons regenerate to topographically appropriate regions of the dorsal horn with artemin treatment. Projections of regenerated muscle and cutaneous myelinated sensory afferents are restricted to the correct spinal segments and to appropriate regions within spinal gray matter. Regenerated unmyelinated axons expressing calcitonin gene-related peptide project only to superficial laminae of the dorsal horn, where uninjured nociceptive afferents project normally. In contrast, intraventricular infusion of a soluble form of the Nogo receptor that blocks the action of several myelin-associated inhibitory proteins promotes relatively unrestricted regeneration of sensory axons throughout the dorsal white and gray matter of the spinal cord. These results demonstrate that cues capable of guiding regenerating axons to appropriate spinal targets persist in the adult mammalian cord, but only some methods of stimulating regeneration allow the use of these cues by growing axons.artemin | central nervous system regeneration | dorsal root | soluble Nogo receptor peptide | specificity G rowth of damaged axons in the adult spinal cord is inhibited by the presence of myelin-associated proteins, up-regulation of proteoglycan expression, and the absence of appropriate growth factors. Several agents that can partially overcome this inhibition permit some regeneration of spinal axons in contusion or transaction models of spinal cord injury (SCI) (1-4); however, the limited regeneration and difficulty in labeling specific subclasses of axons with known projection patterns within the spinal cord have impeded progress in determining whether these regenerated projections are specific.The regeneration of sensory axons into the spinal cord after dorsal root (DR) crush provides a useful preparation for assessing the precision with which regenerating axons project back to appropriate target areas within the central nervous system (CNS). Regrowth of damaged sensory axons within the spinal cord can be visualized by injecting neurotracers into peripheral nerves. Identification of individual classes of axons can be achieved by making injections close to target tissues where nerve branches contain single classes of sensory afferents. Because only the DRs are damaged, the architecture of the spinal cord is left intact, allowing clear identification of the central projections of regenerated axons.Without treatment, sensory axons regenerate only to the DR entry zone (DREZ), where they encounter inhibitory barriers within the CNS (5, 6). Application of two agents-a soluble Nogo receptor peptide (sNgR), which binds to Nogo receptor ligands and abrogates their inhibitory effect (7), and artemin (ART), a member of the glial-derived neurotrophic factor familypromote robust regeneration of sensory axons after DR crush (8, 9). The specificity of projections of specific classes of...

show abstract

Section: Resultsmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 96%

mentioning

confidence: 99%

See 2 more Smart Citations

Topographically specific regeneration of sensory axons in the spinal cord

Harvey

Gong

Rossomando

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Application of neurotrophic factors acting via tyrosine kinase receptors has shown substantially enhanced regeneration (Ramer et al, 2000;Wang et al, 2008;Harvey et al, 2010), even functional recovery with the systemic administration of artemin , although these results await independent replication. Future studies will test whether a combination of RAF activation with trophic growth factors can further enhance axon regeneration and reinnervation of presumptive targets in the spinal cord.…”

Section: Methodsmentioning

confidence: 99%

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

O’Donovan¹,

Ma²,

Guo³

et al. 2014

J Cell Biol

View full text Add to dashboard Cite

Activation of intrinsic growth programs that promote developmental axon growth may also facilitate axon regeneration in injured adult neurons. Here, we demonstrate that conditional activation of B-RAF kinase alone in mouse embryonic neurons is sufficient to drive the growth of long-range peripheral sensory axon projections in vivo in the absence of upstream neurotrophin signaling. We further show that activated B-RAF signaling enables robust regenerative growth of sensory axons into the spinal cord after a dorsal root crush as well as substantial axon regrowth in the crush-lesioned optic nerve. Finally, the combination of B-RAF gain-of-function and PTEN loss-of-function promotes optic nerve axon extension beyond what would be predicted for a simple additive effect. We conclude that cell-intrinsic RAF signaling is a crucial pathway promoting developmental and regenerative axon growth in the peripheral and central nervous systems.

show abstract

Sciatic nerve injury in adult rats causes distinct changes in the central projections of sensory neurons expressing different glial cell line‐derived neurotrophic factor family receptors

Keast

Forrest

Osborne

2010

J of Comparative Neurology

View full text Add to dashboard Cite

Most small unmyelinated neurons in adult rat dorsal ganglia (DRG) express one or more of the coreceptors targeted by glial cell line-derived neurotrophic factor (GDNF), neurturin and artemin (GFRα1, GFRα2 and GFRα3 respectively). The function of these GDNF family ligands (GFLs) is not fully elucidated but recent evidence suggests GFLs could function in sensory neuron regeneration after nerve injury and peripheral nociceptor sensitisation. In this study, we used immunohistochemistry to determine if the DRG neurons targeted by each GFL change after sciatic nerve injury. We compared complete sciatic nerve transection and the chronic constriction model and found the pattern of changes incurred by each injury was broadly similar. In lumbar spinal cord, there was a widespread increase in neuronal GFRα1 immunoreactivity (IR) in the L1-6 dorsal horn. GFRα3-IR also increased but in a more restricted area. In contrast, GFRα2-IR decreased in patches of superficial dorsal horn and this loss was more extensive after transection injury. No change in calcitonin gene-related peptide-IR was detected after either injury. Analysis of double-immunolabelled L5 DRG sections suggested the main effect of injury on GFRα1-and GFRα3-IR was to increase expression in both myelinated and unmyelinated neurons. In contrast, no change in basal expression of GFRα2-IR was detected in DRG by analysis of fluorescence intensity and there was a small but significant reduction in GFRα2-IR neurons. Our results suggest the DRG neuronal populations targeted by GDNF, neurturin or artemin, and the effect of exogenous GFLs could change significantly after a peripheral nerve injury.

show abstract

Persistent restoration of sensory function by immediate or delayed systemic artemin after dorsal root injury

Cited by 90 publications

References 46 publications

Topographically specific regeneration of sensory axons in the spinal cord

Topographically specific regeneration of sensory axons in the spinal cord

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

Sciatic nerve injury in adult rats causes distinct changes in the central projections of sensory neurons expressing different glial cell line‐derived neurotrophic factor family receptors

Contact Info

Product

Resources

About