STAT3 phosphorylation in injured axons before sensory and motor neuron nuclei: potential role for STAT3 as a retrograde signaling transcription factor.

STAT3 is a latent transcription factor that is activated by plasma membrane growth factor receptor complexes. Conditional gene disruption data indicate that it contributes to the survival of cranial motor neurons after peripheral nerve lesion. In agreement, levels of activated STAT3 (Tyr705-phosphorylated STAT3) have been shown to increase in the nuclei of adult cranial motor neurons during their regeneration after the same injury. The data presented here demonstrate that STAT3 is similarly but not identically affected in sciatic motor neurons after sciatic nerve injury. In addition, we find that sensory neuron nuclei also display an analogous increase in activated STAT3, thereby supporting a role for STAT3 in the survival and regeneration of these cells. Most interesting, the present data indicate that peripheral nerve lesion leads to a very rapid activation of STAT3 in axons at the lesion site. This response increases during the first 24 hours after injury and extends back to the motor and sensory neurons such that phospho-STAT3-immunoreactive axons are first detected in the dorsal root ganglia and ventral spinal cord at the same postlesion time intervals at which the activated STAT3 is first detected in the neuronal nuclei. Together these data raise the possibility that axonal STAT3, activated at the injury site, acts as a retrograde signaling transcription factor, which promotes the survival and regeneration of both sensory and motor neurons.