Sphingosine 1-Phosphate Receptor 1 Modulates CNTF-Induced Axonal Growth and Neuroprotection in the Mouse Visual System.

Sandrine Joly,Vincent Pernet,Deniz Dalkara

doi:10.1155/2017/6818970

Abstract

The lack of axonal regeneration and neuronal cell death causes permanent neurological deficits in the injured CNS. Using the classical CNS injury model of optic nerve crush in mice, ciliary neurotrophic factor (CNTF) was found to stimulate retinal ganglion cell (RGC) survival and axonal growth, but in an incomplete fashion. The elucidation of molecular mechanisms impairing CNTF-induced axonal regeneration is paramount to promote visual recovery. In the present study, we sought to evaluate the contribution of sphingosine 1-phosphate receptor 1 (S1PR1) to the neuroprotective and regenerative effects of CNTF. The transduction of retinal cells with adeno-associated viruses (AAV) allowed to activate CNTF/signal transducer and activator of transcription 3 (Stat3) signaling and to modulate S1PR1 expression in RGCs. Our results showed that CNTF/Stat3 prevented injury-induced S1PR1 downregulation. Silencing S1PR1 in RGCs significantly enhanced CNTF-induced axonal growth in the injured optic nerve. In contrast, RGC survival was markedly decreased when S1PR1 was repressed with viral vectors. The level of phosphorylated Stat3 (P-Stat3), an intracellular mediator of CNTF, did not fluctuate after S1PR1 inhibition and CNTF stimulation. Collectively, these results suggest that S1PR1 acts as a major regulator of retinal neuron survival and restricts the RGC growth response induced by CNTF.

Highlights

Optic nerve axon damage is responsible for visual deficits in ophthalmic diseases such as glaucoma
The injection of ShH10.ciliary neurotrophic factor (CNTF), a virus preferentially infecting Müller glia, allowed to detect a brighter signal for P-signal transducer and activator of transcription 3 (Stat3) and sphingosine 1-phosphate receptor 1 (S1PR1) in injured retinal ganglion cell (RGC) compared with control ShH10.Empty virus (Figures 3(a) and 3(b))
We found that selective infection of RGCs with AAV2.Stat3 construct was sufficient to promote axonal growth in the crushed optic nerve [7]

Summary

Introduction

Optic nerve axon damage is responsible for visual deficits in ophthalmic diseases such as glaucoma. In this ocular pathology, permanent vision loss is largely due to the lack of axonal regeneration in the adult optic nerve and retinal ganglion cell (RGC) death [1,2,3]. The failure of axon regeneration is attributable to inhibitory molecules present in the environment of the injured optic nerve and to the intrinsically weak ability of adult neurons to activate a growth program [5,6,7,8]. Growth-promoting molecules released by immune and glial cells were identified in the retina. The regenerative properties of CNTF are highly dependent on the intracellular activation of the signal transducer and activator of transcription 3 (Stat3) transcription

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Discussion

Conclusion