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Yan Wang, Akintomide Apara, Murray Blackmore, Dale Brown, Michelle LeBlanc, Alyson Trillo, Jeffrey Goldberg; Regulation of Krüppel-like Transcription Factor (KLF’s) Family Members Promotes Potent Axon Regeneration in the Adult Rat Optic Nerve. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4693.
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RGC axons fail to regenerate after optic nerve injury. In our previous study, we found that KLF family members regulate intrinsic axon growth ability of retinal ganglion cells (RGCs) during development. In this study, we asked whether knocking down multiple KLFs, which suppress axon growth ability, and overexpressing KLF7, which promote axon growth ability, would enhance axon regeneration in adult rats after optic nerve injury.
The expression of KLF-9, -13, -16 and PTEN in adult rat RGCs were knocked down by intravitreal injection of AAV2-shRNA, and the expression of KLF-7 was up-regulated by intravitreal injection of AAV2-VP16-KLF7. Optic nerve crush was performed two weeks after virus injection. 14 days after optic nerve crush, full-length of optic nerves to the optic chiasm were dissected and prepared for cryosection. Retrograde labeling with Fluorogold and anterograde labeling with Cholera toxin B were used to measure RGC survival and axon regeneration, respectively.
Compared to controls, simultaneous application of AAV2-shRNA anti KLF-9, -13, -16 significantly increased RGC survival up to 50%. Similar RGC protection was observed in AAV2-shRNA-anti PTEN treated animals. The number of regenerating axons in all experimental groups was significantly more than in controls. More axon regeneration was observed after KLF9 knockdown. Large numbers of regenerating axons crossed the optic chiasm, the majority of which extended contralaterally while a few axons grew ipsilaterally.
Knocking down KLF-9, -13, -16 by shRNA and overexpression of KLF7 in adult rat RGCs, increase RGC survival and induce axon regeneration after optic nerve injury. Our findings indicate the potential translational application of these treatments for optic nerve traumatic injury or degenerative diseases.
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