Topographically specific regeneration of sensory axons in the spinal cord

Abstract

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...

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

“…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.…”

Artemin promotes functional long-distance axonal regeneration to the brainstem after dorsal root crush

“…fact that crushed sensory axons stop regenerating at the DR entry zone, the transitional zone between the peripheral nervous system and CNS (6,10). In animals treated with systemic ARTN104, substantial numbers of labeled puncta in the ipsilateral CN were evident at 6 mo after DR crush (Fig.…”

“…Our initial experiments were carried out in animals treated with ARTN104, a truncated version of ARTN with nine N-terminal amino acids removed to reduce binding to heparan sulfate proteoglycans (12). Because of constraints on our supply of ARTN104, we conducted subsequent experiments using ARTN113, a longer form of ARTN containing 113 amino acids that we had used in previous studies (3,6).…”

“…Fine touch and proprioceptive neurons with cell bodies in the DR ganglion (DRG) provide monosynaptic input to neurons in the dorsal column nuclei. These neurons can be traced using transganglionic labeling methods and are easily studied electrophysiologically, making this an ideal injury model for investigating functional regeneration from the brachial SC to the brainstem.Previous studies demonstrated that a 2-wk systemic treatment with the neurotrophic factor artemin (ARTN) promotes topographically specific regeneration of both myelinated and unmyelinated sensory axons into the SC at 1 mo after DR crush (3,6). This results in persistent recovery of simple behavioral tasks and of electrophysiological function in the SC.…”

“…Previous studies demonstrated that a 2-wk systemic treatment with the neurotrophic factor artemin (ARTN) promotes topographically specific regeneration of both myelinated and unmyelinated sensory axons into the SC at 1 mo after DR crush (3,6). This results in persistent recovery of simple behavioral tasks and of electrophysiological function in the SC.…”