title: Promoting axon regeneration in the adult CNS by modulation of the melanopsin/GPCR signaling.
abstract: Cell-type-specific G protein-coupled receptor (GPCR) signaling regulates distinct neuronal responses to various stimuli and is essential for axon guidance and targeting during development. However, its function in axonal regeneration in the mature CNS remains elusive. We found that subtypes of intrinsically photosensitive retinal ganglion cells (ipRGCs) in mice maintained high mammalian target of rapamycin (mTOR) levels after axotomy and that the light-sensitive GPCR melanopsin mediated this sustained expression. Melanopsin overexpression in the RGCs stimulated axonal regeneration after optic nerve crush by up-regulating mTOR complex 1 (mTORC1). The extent of the regeneration was comparable to that observed after phosphatase and tensin homolog (Pten) knockdown. Both the axon regeneration and mTOR activity that were enhanced by melanopsin required light stimulation and Gq/11 signaling. Specifically, activating Gq in RGCs elevated mTOR activation and promoted axonal regeneration. Melanopsin overexpression in RGCs enhanced the amplitude and duration of their light response, and silencing them with Kir2.1 significantly suppressed the increased mTOR signaling and axon regeneration that were induced by melanopsin. Thus, our results provide a strategy to promote axon regeneration after CNS injury by modulating neuronal activity through GPCR signaling.
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Center of Systems Biology and Human Health, School of Science and Institute for Advance Study, The Hong Kong University of Science and Technology, Hong Kong, China;
authors.forename: Songshan
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Center of Systems Biology and Human Health, School of Science and Institute for Advance Study, The Hong Kong University of Science and Technology, Hong Kong, China;
authors.forename: Chao
authors.initials: C
authors.lastname: Yang
authors.affiliation: Institute of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China;
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Center of Systems Biology and Human Health, School of Science and Institute for Advance Study, The Hong Kong University of Science and Technology, Hong Kong, China;
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Center of Systems Biology and Human Health, School of Science and Institute for Advance Study, The Hong Kong University of Science and Technology, Hong Kong, China;
authors.forename: Xuejie
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China;
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Center of Systems Biology and Human Health, School of Science and Institute for Advance Study, The Hong Kong University of Science and Technology, Hong Kong, China;
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Songshan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China;
authors.forename: Yung Hou
authors.initials: YH
authors.lastname: Wong
authors.affiliation: Institute of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China;
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China; Center of Systems Biology and Human Health, School of Science and Institute for Advance Study, The Hong Kong University of Science and Technology, Hong Kong, China; kailiu@ust.hk.
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
mesh_terms: D000818:Animals; D001369:Axons; D002490:Central Nervous System / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009416:Nerve Regeneration; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D017299:Rod Opsins / Q000378:metabolism*; D015398:Signal Transduction; D000099210:Melanopsin
chemical_list: D051059:PTEN Phosphohydrolase; D043562:Receptors, G-Protein-Coupled; D017299:Rod Opsins; D000099210:Melanopsin; C487757:Pten protein, mouse
keywords: GPCR; axon regeneration; mTOR; melanopsin; neuronal activity
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