Wnt signaling promotes axonal regeneration following optic nerve injury in the mouse

Abstract

Adult mammalian CNS axons generally do not regenerate, creating an obstacle to effective repair and recovery after neuronal injury. The canonical Wnt/β-catenin signaling pathway is an essential signal transduction cascade that regulates axon growth and neurite extension in the developing mammalian embryo. In this study, we investigated whether a Wnt/β-catenin signaling activator could be repurposed to induce regeneration in the adult CNS after axonal injury. We used a retinal ganglion cell (RGC) axon crush injury model in a transgenic Wnt reporter mouse, and intravitreal injections were used to deliver Wnt3a or saline to the RGC cell bodies within the retina. Our findings demonstrated that Wnt3a induced Wnt signaling in RGCs and resulted in significant axonal regrowth past the lesion site when measured at two and four weeks post-injury. Furthermore, Wnt3a-injected eyes showed increased survival of RGCs and significantly higher PERG amplitudes compared to the control. Additionally, Wnt3a-induced axonal regeneration and RGC survival was associated with elevated activation of the transcription factor Stat3, and reducing expression of Stat3 using a conditional Stat3 knock-out mouse line led to diminished Wnt3a-dependent axonal regeneration and RGC survival. Therefore, these findings reveal a novel role for retinal Wnt signaling in axonal regrowth and RGC survival following axonal injury, which may lead to the development of novel therapies for axonal regeneration.

Neuroprotective Effects of Curcumin-Loaded Emulsomes on Laser Axotomy-Induced CNS Injury Model

“…Following an axonal injury, Wnt signaling could promote the neuronal survival and regeneration of CNS axons on retinal ganglion cells [66]. The neuroprotective effects of Wnt signaling includes prevention of excitotoxicity and promotion of axonal growth within the adult spinal cord and sensory neurons following the injury [66][67][68][69][70][71]. In our study, curcumin treatment signi cantly upregulated the Wnt3a on control cells as expected (pvalue: 0.00 when compared to untreated control cells).…”

“…To date, various studies have shown that use of neuroprotective agents resulted in up-regulation of the canonical Wnt3a signaling, and thus, further enhances the neurogenesis [24,[63][64][65]. Following an axonal injury, Wnt signaling could promote the neuronal survival and regeneration of CNS axons on retinal ganglion cells [66]. The neuroprotective effects of Wnt signaling includes prevention of excitotoxicity and promotion of axonal growth within the adult spinal cord and sensory neurons following the injury [66][67][68][69][70][71].…”

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

“…These included, besides CDKN2A and CDKN2B , developmentally relevant genes, CDKN1B , FGF2 , SOX11 , FOS , JUNB , STAT1 , STAT3 , VEGF , BDNF , SCNG, and ATF3 . Of these, the majority is involved in RGC development/survival/regeneration such as FGF2 , SOX11 , SNCG , STAT3 , VEGF , BDNF , and ATF3 . Other common genes included CEBPB , CP , FAS , EDNRB , ANXA1 , NEFL , TP53 , TXN , TXN2 , TBK1 , SOD1 , and OPTN .…”

Expression and Manipulation of the APC-β-Catenin Pathway During Peripheral Neuron Regeneration

“…As expected through its interactions, APC influences proliferation, apoptosis, cell adhesion, and migration 7 . APC is strongly expressed in both the developing and adult nervous system 22 .…”