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Amit Patel, Kevin Park, Abigail Hackam; Wnt signaling promotes retinal ganglion cell survival and axonal regeneration in mouse models of optic nerve injury. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1755.
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© ARVO (1962-2015); The Authors (2016-present)
Optic neuropathies are a family of diseases that result in axonal damage of retinal ganglion cells (RGCs). As part of the central nervous system, the axons do not self-regenerate, leading to RGC cell death and vision loss. The canonical Wnt/β-catenin signaling pathway is known to regulate axon growth and neurite extension in the developing mammalian nervous system. In this study, we tested the hypothesis that Wnt signaling could be repurposed to increase RGC survival and induce axonal growth in the adult optic nerve after injury.
We tested the role of Wnt signaling in axonal regeneration using the optic nerve crush model in transgenic Wnt reporter mice. Recombinant Wnt3a protein was intravitreally injected into the mouse eye, in order to induce Wnt signaling. Optic nerves were crushed at the same time as injection to induce axonal injury. Optic nerves were labelled and collected at 2 and 4 week timepoints after injury to assess for regeneration. RGC survival and function were measured by retinal flatmount counting and pattern electroretinography, respectively. To test the mechanism of Wnt signaling changes in the axonal regeneration, we examined the Stat3 pathway using floxed Stat3 mice.
We found 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 (p<0.05, n=6). Furthermore, Wnt3a-injected eyes showed increased survival and function of RGCs and significantly higher PERG amplitudesfollowing optic nerve injury compared to the control (p<0.05, n=3-4). Additionally, Wnt3a-induced axonal regeneration and RGC survival was associated with activation of Stat3 signaling (p<0.05, n=4), and knocking out Stat3 in the floxed mice led to reduced Wnt3a-dependent axonal regeneration and RGC survival (p<0.05, n=5).
These findings show a novel role for Wnt signaling in the adult retina as a neuroprotective and regenerative mechanims for RGCs and their axons following optic nerve injury. These results may lead to the development of novel therapies for optic neuropathies and axonal injury related diseases.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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