Exogenous CNTF stimulates axon regeneration of retinal ganglion cells partially via endogenous CNTF

Mol Cell Neurosci. 2009 Jun;41(2):233-46. doi: 10.1016/j.mcn.2009.03.002. Epub 2009 Mar 28.


Intravitreal injections of exogenous CNTF stimulate axon regeneration of RGCs in vivo. Nevertheless, controversy exists over the ability of exogenous CNTF to directly stimulate axon regeneration of mature RGCs. Here we demonstrate that CNTF potently stimulated axon outgrowth of mature RGCs in culture in a JAK/STAT3- and PI3K/AKT-signaling pathway-dependent fashion and stronger than oncomodulin. Additional cAMP elevation or inhibition of MAPK activity increased these effects. In vivo intravitreal injections of exogenous CNTF induced endogenous CNTF expression in astrocytes in a manner that depended on the MAPK/ERK-signaling pathway activation. Reduction of endogenous CNTF expression by MAPK/ERK pathway inhibitors or its absence in CNTF deficient mice markedly reduced the neurite growth-promoting effects of exogenous CNTF. These data demonstrate that CNTF is a potent axon growth-promoting factor for mature RGCs. However, exogenously applied CNTF stimulates RGCs in vivo partially indirectly via a mechanism that depends on astrocyte-derived CNTF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / metabolism
  • Axons* / drug effects
  • Axons* / physiology
  • Cells, Cultured
  • Ciliary Neurotrophic Factor / genetics
  • Ciliary Neurotrophic Factor / metabolism*
  • Ciliary Neurotrophic Factor / pharmacology*
  • Enzyme Inhibitors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Janus Kinases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Nerve Regeneration* / drug effects
  • Nerve Regeneration* / physiology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Retinal Ganglion Cells* / cytology
  • Retinal Ganglion Cells* / drug effects
  • Retinal Ganglion Cells* / physiology
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / physiology


  • Ciliary Neurotrophic Factor
  • Enzyme Inhibitors
  • Recombinant Proteins
  • STAT3 Transcription Factor
  • Phosphatidylinositol 3-Kinases
  • Janus Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases