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Updated: Feb 15, 2026
A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
Published on: June 8, 2022
Sphingosine 1-phosphate receptor 1 is required for retinal ganglion cell survival after optic nerve trauma
Sandrine Joly1, Vincent Pernet1
1CUO-Recherche, Centre de recherche du CHU de Québec and Département d'ophtalmologie, Faculté de médecine, Université Laval, Quebec City, Quebec, Canada.
Abstract:
In this study, we used a classical optic nerve injury model to address the function of the sphingosine 1-phosphate (S1P)-S1P receptor (S1PR) axis in retinal ganglion cell (RGC) death and axonal growth. After lesion, the expression of S1PR1 was generally reduced in axotomized RGCs but persisted in αRGCs, a subpopulation of injury-resistant RGCs. Silencing S1PR1 with an adeno-associated virus serotype 2 (AAV2) containing a shRNA specific to S1PR1 (AAV2.shRNA-S1PR1) exacerbated the loss of RGCs induced by optic nerve crush; the rate of RGC survival was decreased by more than 24% in retinae infected with AAV2.shRNA-S1PR1 compared with AAV2.shRNA-scrambled or AAV2.GFP control treatments. In the superior and temporal regions of the retina, cell death rose by more than ~ 35% and ~ 50%, respectively, in comparison with control groups. In the optic nerve, S1PR1 silencing markedly reduced axonal sprouting after the lesion relative to control animals. Early after optic nerve crush, 67% of αRGCs stained for osteopontin were lost in retinae infected with AAV2.shRNA-S1PR1, whereas the number of intrinsically photosensitive RGCs expressing melanopsin, another injury-resistant RGC type, was not affected. Moreover, retinal infection with AAV2.shRNA-S1PR1 down-regulated mammalian target of rapamycin pathway activation in αRGCs. Together, our results reveal that S1PR1 contributes to survival and growth mechanisms in injured RGCs by regulating the mammalian target of rapamycin pathway. The role of sphingosine 1-phosphate receptor 1 (S1PR1) was studied in retinal ganglion cell survival and axonal growth after optic nerve injury. After axonal damage, S1PR1 expression was decreased in retinal neurons. Viral-mediated S1PR1 down-regulation enhanced injury-induced cell death and reduced spontaneous axonal growth. In injury-resistant retinal neurons, the activation of mTOR signalling was down-regulated by silencing S1PR1, suggesting an important role for S1PR1 in neuronal growth and survival mechanisms in vivo.
Insights
Sphingosine 1-phosphate receptor 1 (S1PR1) is crucial for retinal ganglion cell (RGC) survival and axonal growth after optic nerve injury. Silencing S1PR1 increases RGC death and reduces nerve regeneration, highlighting its neuroprotective role.
Area of Science:
- Neuroscience
- Ophthalmology
- Cell Biology
Background:
- Optic nerve injury leads to retinal ganglion cell (RGC) death and impaired axonal regeneration.
- The sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) axis is implicated in neuronal survival and repair.
- Specific roles of S1PR1 in RGCs post-injury remain to be fully elucidated.
Purpose of the Study:
- To investigate the function of the S1P-S1PR axis, particularly S1PR1, in RGC survival and axonal growth following optic nerve injury.
- To determine the impact of S1PR1 modulation on RGC death and regeneration in vivo.
Main Methods:
- Utilized a classical optic nerve crush injury model in rodents.
- Employed adeno-associated virus serotype 2 (AAV2) vectors to deliver shRNA targeting S1PR1 (AAV2.shRNA-S1PR1) for gene silencing.
- Assessed RGC survival, axonal sprouting, and mammalian target of rapamycin (mTOR) pathway activation in response to S1PR1 silencing.
Main Results:
- Optic nerve crush reduced S1PR1 expression in RGCs, but it persisted in injury-resistant αRGCs.
- AAV2.shRNA-S1PR1 treatment significantly exacerbated RGC loss (over 24% decrease in survival) and reduced axonal sprouting compared to controls.
- S1PR1 silencing led to a significant loss of osteopontin-positive αRGCs and down-regulated mTOR pathway activation in these cells.
Conclusions:
- S1PR1 plays a critical role in promoting RGC survival and axonal regeneration after optic nerve injury.
- S1PR1 signaling contributes to neuronal resilience by regulating the mTOR pathway, particularly in injury-resistant RGC subtypes.
- Targeting S1PR1 may offer a therapeutic strategy for enhancing recovery following optic nerve damage.
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