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The Journal of Neuroscience, February 16, 2005, 25(7):1645-1653; doi:10.1523/JNEUROSCI.3269-04.2005

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Development/Plasticity/Repair
Conditioning Injury-Induced Spinal Axon Regeneration Requires Signal Transducer and Activator of Transcription 3 Activation

Jin Qiu, William B. J. Cafferty, Stephen B. McMahon, and Stephen W. N. Thompson

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

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.

Key words: STAT; regeneration; condition lesion; gp130 cytokines; axon growth; sensory system

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Received Aug 10, 2004; revised December 12, 2004; accepted December 16, 2004.

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