Abstract
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.
Highlights
(CNS), mature retinal ganglion cells (RGCs) are incapable of regenerating damaged axons after injury, but instead undergo apoptotic cell death
We and others have previously demonstrated that ciliary neurotrophic factor (CNTF)- and inflammatory stimulation (IS)-induced transformation of RGCs into an active regenerative state is associated with phosphorylation and nuclear localization of STAT3 in these neurons, and in other retinal cells.[19,22,25,39]
Intravitreal injection of the JAK inhibitor AG490, which partially blocked STAT3 phosphorylation in the inner retina, reportedly compromised CNTF- and, to some extent, IS-mediated axon regeneration.[19,25,27]. These data suggest an important role of JAK signaling, it remained elusive whether subsequent neuronal STAT3 activation is required for the transformation of RGCs into a regenerative state or whether AG490 injection may have indirectly compromised regeneration by affecting other cells
Summary
Depletion of STAT3 expression in RGCs by AAV2. To elucidate the role of STAT3 in RGCs during IS-induced axonal regeneration, we used a conditional knockdown approach. IS reportedly transforms injured RGCs into an active regenerative state, indicated by the expression of regeneration-associated genes and spontaneous neurite outgrowth of cultured RGCs after prior in vivo treatment.[19] in the course of IS, STAT3 is activated in RGCs as well as in cells of the fiber and inner nuclear layer (Figure 1c and Muller et al.[19] and Hauk et al.18), raising the question whether STAT3 expression/activation in RGCs or in other retinal cells is required for these IS-induced effects To address this question, STAT3floxed mice were intravitreally injected with either AAV2-Cre or AAV2-GFP and 2 weeks later subjected to either ONC or ONC þ IS. The number of axons growing 0.5, 1 or 1.5 mm beyond the lesion site was reduced by B80% compared with AAV2-GFP-treated control mice (Figures 4a and b), suggesting that STAT3 expression in RGCs is essential for IS-mediated axonal regeneration in vivo
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