Ectopic expression of melanopsin promotes axonal regeneration in retinal ganglion cells via cAMP and TRPC signaling
- 1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205
- 2Retina Section, Department of Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 201318, China
Abstract
In mammals, retinal ganglion cells (RGCs) show very minor axonal regeneration following axotomy. Despite genetic and pharmacological efforts to promote this regeneration, progress remains slow and limited, especially in overcoming potentially cell-type-specific barriers. In this paper, we virally expressed melanopsin (OPN4), which is the native photopigment in intrinsically-photosensitive RGCs (ipRGCs), broadly in RGCs. IpRGCs are known to show relative resistance to degeneration and axonal loss after injury. We correlated the exogenous-melanopsin-mediated intrinsic light responses of the successfully infected RGCs (referred to as +OPN4RGCs) with their ability to show axonal regeneration after an optic-nerve crush. Specifically, we found +OPN4RGCs to show functional rhabdomeric and ciliary motifs of phototransduction as we previously found in ipRGCs. +OPN4αRGCs (the largest RGCs in the retina) exhibited light-triggered fast (via TRPC signaling) and slow (via cAMP signaling) response components, whereas +OPN4non-αRGC responses comprised predominantly just a fast component. Genetic ablation of TRPC channels (TRPC6/7) or group II adenylyl cyclase (AC2/4/7) to abolish the fast or the slow response component, respectively, largely attenuated the axonal regeneration of +OPN4αRGCs in the optic-nerve-crush model. At the same time, administration of cell-permeant cAMP not only rescued the AC2/4/7-knock-out phenotype in +OPN4αRGCs but also potentiated axonal regeneration in some +OPN4non-αRGCs, thus, possibly overcoming the potential subtype-specific barrier to axonal regeneration. Our results reveal an important role of joint TRPC- and cAMP-signaling in +OPN4RGC axonal regeneration.
Related
- Neuropeptide Signaling Promotes Stem-Cell Driven Regeneration in Planarians
- A blastema in sea star larvae integrates wound signaling to drive regeneration-specific and developmental gene expression patterns.
- Temporal patterns of melanopsin-evoked calcium signaling engage NF-κB-associated transcriptional and phosphoproteomic responses
- SEX-DEPENDENT MODULATION OF WHOLE BRAIN cFOS EXPRESSION BY LIGHT AND MELANOPSIN IN THE MOUSE
- Lateralized Tenm4 expression biases visual performance and modulates axonal growth and pre-synapse size in retinal ganglion cells
BibTeX
@article{li2026ectopic,
title = {{Ectopic expression of melanopsin promotes axonal regeneration in retinal ganglion cells via cAMP and TRPC signaling}},
author = {Guang Li and Zuying Chai and Sonya Zhang and Yanxi Ren and King-Wai Yau and Sihan Li},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2628062123},
url = {https://doi.org/10.1073/pnas.2628062123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Ectopic expression of melanopsin promotes axonal regeneration in retinal ganglion cells via cAMP and TRPC signaling
AU - Guang Li
AU - Zuying Chai
AU - Sonya Zhang
AU - Yanxi Ren
AU - King-Wai Yau
AU - Sihan Li
PY - 2026
DA - 2026/10/27
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2628062123
UR - https://doi.org/10.1073/pnas.2628062123
AB - In mammals, retinal ganglion cells (RGCs) show very minor axonal regeneration following axotomy. Despite genetic and pharmacological efforts to promote this regeneration, progress remains slow and limited, especially in overcoming potentially cell-type-specific barriers. In this paper, we virally expressed melanopsin (OPN4), which is the native photopigment in intrinsically-photosensitive RGCs (ipRGCs), broadly in RGCs. IpRGCs are known to show relative resistance to degeneration and axonal loss after injury. We correlated the exogenous-melanopsin-mediated intrinsic light responses of the successfully infected RGCs (referred to as +OPN4RGCs) with their ability to show axonal regeneration after an optic-nerve crush. Specifically, we found +OPN4RGCs to show functional rhabdomeric and ciliary motifs of phototransduction as we previously found in ipRGCs. +OPN4αRGCs (the largest RGCs in the retina) exhibited light-triggered fast (via TRPC signaling) and slow (via cAMP signaling) response components, whereas +OPN4non-αRGC responses comprised predominantly just a fast component. Genetic ablation of TRPC channels (TRPC6/7) or group II adenylyl cyclase (AC2/4/7) to abolish the fast or the slow response component, respectively, largely attenuated the axonal regeneration of +OPN4αRGCs in the optic-nerve-crush model. At the same time, administration of cell-permeant cAMP not only rescued the AC2/4/7-knock-out phenotype in +OPN4αRGCs but also potentiated axonal regeneration in some +OPN4non-αRGCs, thus, possibly overcoming the potential subtype-specific barrier to axonal regeneration. Our results reveal an important role of joint TRPC- and cAMP-signaling in +OPN4RGC axonal regeneration.
SN - 0027-8424
SN - 1091-6490
ER -