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The Journal of Neuroscience, September 13, 2006, 26(37):9512-9519; doi:10.1523/JNEUROSCI.2160-06.2006

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Development/Plasticity/Repair
Suppressor of Cytokine Signaling-3 Suppresses the Ability of Activated Signal Transducer and Activator of Transcription-3 to Stimulate Neurite Growth in Rat Primary Sensory Neurons

Tizong Miao,^1 * Dongsheng Wu,^1 * Yi Zhang,¹ Xuenong Bo,¹ Maria Cristina Subang,² Ping Wang,³ and Peter M. Richardson¹

Centres for ¹Neuroscience, ²Bone and Joint, and ³Gastroenterology, Barts and the London Queen Mary's School of Medicine, University of London, London E1 2AT, United Kingdom

Correspondence should be addressed to Dr. Peter M. Richardson at the above address. Email: p.richardson{at}qmul.ac.uk

The actions of the neuropoietic cytokines are mediated by the gp130 receptor, which activates several signaling molecules including the transcription factor STAT3 (signal transducer and activator of transcription), which, in turn, is subject to feedback inhibition by SOCS3 (suppressor of cytokine signaling). Activation of the gp130 receptor has been implicated in axonal growth particularly during regeneration, but the specific contribution of STAT3 is the subject of conflicting reports. Measurements of SOCS3 mRNA in rat dorsal root ganglia showed a significant induction in this inhibitory molecule after peripheral nerve injury. The functions of STAT3 and SOCS3 in adult rat primary sensory neurons were investigated in vitro through transduction of lentiviruses yielding a conditionally activated STAT3, native SOCS3, or a mutant SOCS3 with dominant-negative actions. The SOCS3 construct was effective in inhibiting tyrosine phosphorylation of STAT3 in a neuroblastoma cell line and in blocking nuclear accumulation of endogenous STAT3 or of the conditionally activated STAT3 chimera in primary sensory neurons. In such neurons, transduction and activation of STAT3 enhanced neurite growth, transduction with SOCS3 reduced neurite outgrowth, and transduction with mutant SOCS3 enhanced neurite growth, at least under basal conditions. In conclusion, STAT3 signaling is beneficial to axonal growth through activating transcription of unidentified genes, and SOCS3 is detrimental to axonal growth through inhibition of STAT3 and/or other transcription factors.

Key words: SOCS3; STAT3; neurite growth; primary sensory neuron; cytokine; conditioning

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Received May 22, 2006; revised Aug. 7, 2006; accepted Aug. 10, 2006.

Correspondence should be addressed to Dr. Peter M. Richardson at the above address. Email: p.richardson{at}qmul.ac.uk

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