Conditioning injury-induced spinal axon regeneration requires signal transducer and activator of transcription 3 activation.
Sensory axons in the adult spinal cord do not regenerate after injury. This is essentially because of inhibitory components in the damaged CNS, such as myelin-associated inhibitors and the glial scar. However, if the sciatic nerve is axotomized before injury of the dorsal column, injured axons can regenerate a short distance in the spinal cord. Here, we show that sciatic nerve transection results in time-dependent phosphorylation and activation of the transcription factor, signal transducer and activator of transcription 3 (STAT3), in dorsal root ganglion (DRG) neurons. This effect is specific to peripheral injuries and does not occur when the dorsal column is crushed. Sustained perineural infusion of the Janus kinase 2 (JAK2) inhibitor AG490 to the proximal nerve stump can block STAT3 phosphorylation after sciatic nerve transection and results in reduced growth-associated protein 43 upregulation and compromised neurite outgrowth in vitro. Importantly, in vivo perineural infusion of AG490 also significantly attenuates dorsal column axonal regeneration in the adult spinal cord after a preconditioning sciatic nerve transection. We conclude that STAT3 activation is necessary for increased growth ability of DRG neurons and improved axonal regeneration in the spinal cord after a conditioning injury.
Qiu
Jin
J
Wolfson Centre for Age-Related Diseases, Guy's, King's, and St. Thomas's School of Biomedical Science, King's College London, London SE1 1UL, United Kingdom.
Cafferty
William B J
WB
McMahon
Stephen B
SB
Thompson
Stephen W N
SW
D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D001369:Axons / Q000502:physiology; D019771:Axotomy; D002478:Cells, Cultured / Q000187:drug effects / Q000648:ultrastructure; D002772:Cholera Toxin / Q000008:administration & dosage / Q000633:toxicity; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000502:physiology*; D019922:GAP-43 Protein / Q000096:biosynthesis / Q000235:genetics; D005727:Ganglia, Spinal / Q000503:physiopathology; D015918:Infusion Pumps, Implantable; D053614:Janus Kinase 2; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor; D012584:Sciatic Nerve / Q000293:injuries; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D015534:Trans-Activators / Q000502:physiology*; D020032:Tyrphostins / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D019922:GAP-43 Protein; C494201:Il6st protein, rat; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D050822:Cytokine Receptor gp130; D002772:Cholera Toxin; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2
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