Abstract
Axon regeneration failure accounts for permanent functional deficits following CNS injury in adult mammals. However, the underlying mechanisms remain elusive. In analyzing axon regeneration in different mutant mouse lines, we discovered that deletion of suppressor of cytokine signaling 3 (SOCS3) in adult retinal ganglion cells (RGCs) promotes robust regeneration of injured optic nerve axons. This regeneration-promoting effect is efficiently blocked in SOCS3-gp130 double-knockout mice, suggesting that SOCS3 deletion promotes axon regeneration via a gp130-dependent pathway. Consistently, a transient upregulation of ciliary neurotrophic factor (CNTF) was observed within the retina following optic nerve injury. Intravitreal application of CNTF further enhances axon regeneration from SOCS3-deleted RGCs. Together, our results suggest that compromised responsiveness to injury-induced growth factors in mature neurons contributes significantly to regeneration failure. Thus, developing strategies to modulate negative signaling regulators may be an efficient strategy of promoting axon regeneration after CNS injury.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Animals, Newborn
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Axons / drug effects
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Axons / metabolism
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Axons / pathology
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Carrier Proteins / metabolism
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Cholera Toxin / metabolism
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Ciliary Neurotrophic Factor / genetics
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Ciliary Neurotrophic Factor / pharmacology
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Cytokine Receptor gp130 / deficiency
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Gene Expression Regulation / genetics
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Green Fluorescent Proteins / genetics
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Injections, Intraventricular / methods
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Nerve Regeneration / drug effects
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Nerve Regeneration / genetics*
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Nerve Regeneration / physiology
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Optic Nerve Injuries / drug therapy
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Optic Nerve Injuries / genetics
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Optic Nerve Injuries / physiopathology*
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Organ Culture Techniques
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Retinal Ganglion Cells / pathology
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Retinal Ganglion Cells / physiology
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / deficiency*
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Suppressor of Cytokine Signaling Proteins / physiology
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TOR Serine-Threonine Kinases
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Time Factors
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Tubulin / metabolism
Substances
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Carrier Proteins
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Ciliary Neurotrophic Factor
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Il6st protein, mouse
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Socs3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Tubulin
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beta3 tubulin, mouse
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Cytokine Receptor gp130
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Green Fluorescent Proteins
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Cholera Toxin
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Phosphotransferases (Alcohol Group Acceptor)
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mTOR protein, mouse
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TOR Serine-Threonine Kinases