Neuronal STAT3 activation is essential for CNTF- and inflammatory stimulation-induced CNS axon regeneration.
CNS neurons, such as retinal ganglion cells (RGCs), do not normally regenerate injured axons, but instead undergo apoptotic cell death. Regenerative failure is due to inhibitory factors in the myelin and forming glial scar as well as due to an insufficient intrinsic capability of mature neurons to regrow axons. Nevertheless, RGCs can be transformed into an active regenerative state upon inflammatory stimulation (IS) in the inner eye, for instance by lens injury, enabling these RGCs to survive axotomy and to regenerate axons into the lesioned optic nerve. The beneficial effects of IS are mediated by various factors, including CNTF, LIF and IL-6. Consistently, IS activates various signaling pathways, such as JAK/STAT3 and PI3K/AKT/mTOR, in several retinal cell types. Using a conditional knockdown approach to specifically delete STAT3 in adult RGCs, we investigated the role of STAT3 in IS-induced neuroprotection and axon regeneration. Conditional STAT3 knockdown in RGCs did not affect the survival of RGCs after optic nerve injury compared with controls, but significantly reduced the neuroprotective effects of IS. STAT3 depletion significantly compromised CNTF-stimulated neurite growth in culture and IS-induced transformation of RGCs into an active regenerative state in vivo. As a consequence, IS-mediated axonal regeneration into the injured optic nerve was almost completely abolished in mice with STAT3 depleted in RGCs. In conclusion, STAT3 activation in RGCs is involved in neuroprotection and is a necessary prerequisite for optic nerve regeneration upon IS.
Department of Neurology, Heinrich-Heine-University of Düsseldorf, Merowingerplatz 1a, Düsseldorf, Germany.
M
M
Leibinger
A
A
Andreadaki
H
H
Diekmann
D
D
Fischer
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects; D000229:Dependovirus / Q000378:metabolism; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000187:drug effects*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009900:Optic Nerve / Q000187:drug effects; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*
D020934:Ciliary Neurotrophic Factor; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse