Enhanced Transcriptional Activity and Mitochondrial Localization of STAT3 Co-induce Axon Regrowth in the Adult Central Nervous System

Cell Rep. 2016 Apr 12;15(2):398-410. doi: 10.1016/j.celrep.2016.03.029. Epub 2016 Mar 31.


Signal transducer and activator of transcription 3 (STAT3) is a transcription factor central to axon regrowth with an enigmatic ability to act in different subcellular regions independently of its transcriptional roles. However, its roles in mature CNS neurons remain unclear. Here, we show that along with nuclear translocation, STAT3 translocates to mitochondria in mature CNS neurons upon cytokine stimulation. Loss- and gain-of-function studies using knockout mice and viral expression of various STAT3 mutants demonstrate that STAT3's transcriptional function is indispensable for CNS axon regrowth, whereas mitochondrial STAT3 enhances bioenergetics and further potentiates regrowth. STAT3's localization, functions, and growth-promoting effects are regulated by mitogen-activated protein kinase kinase (MEK), an effect further enhanced by Pten deletion, leading to extensive axon regrowth in the mouse optic pathway and spinal cord. These results highlight CNS neuronal dependence on STAT3 transcriptional activity, with mitochondrial STAT3 providing ancillary roles, and illustrate a critical contribution for MEK in enhancing diverse STAT3 functions and axon regrowth.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Aging / metabolism*
  • Animals
  • Axons / metabolism*
  • Central Nervous System / metabolism*
  • Ciliary Neurotrophic Factor / pharmacology
  • Electron Transport / drug effects
  • Female
  • Gene Deletion
  • Male
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Nerve Regeneration / drug effects
  • PTEN Phosphohydrolase / metabolism
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Protein Domains
  • Protein Transport
  • Pyramidal Tracts / metabolism
  • Retinal Ganglion Cells / drug effects
  • Retinal Ganglion Cells / metabolism
  • STAT3 Transcription Factor / chemistry
  • STAT3 Transcription Factor / metabolism*
  • Structure-Activity Relationship
  • Subcellular Fractions / metabolism
  • Transcription, Genetic*


  • Ciliary Neurotrophic Factor
  • STAT3 Transcription Factor
  • Phosphoserine
  • Adenosine Triphosphate
  • Mitogen-Activated Protein Kinase Kinases
  • PTEN Phosphohydrolase