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L. Yang, D.F. Chen; Robust Regeneration of Severed Optic Nerves into Their Ipsilateral Brain Target in Bcl-2 Overexpressing Mice . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2104.
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Purpose: To determine whether overexpression of Bcl-2 is sufficient to support optic nerve regeneration in vivo in the early neonatal stage, when the brain environment remains permissive for axonal growth, and whether regenerating axons follow the guidance cues to reach the appropriate targets in the brain. Method: Optic nerve crush was performed in wild-type and Bcl-2 transgenic mouse pups at 3 days after birth (P3). To assess optic nerve regeneration, mouse pups were allowed to survive for 1-18 days post-surgery. An anterograde tracer – cholera toxin B subunit conjugated with fluorescein (CTB-F) – was applied intraocularly, immediately after optic nerve crush to label retinal ganglion cell axons. To corroborate the result, immunofluorescent staining with anti-GAP-43 was also applied to reveal regenerating axons in optic nerve sections. Result: In wild-type mice, severed optic nerves failed to regenerate, and most severed axons retracted within 24 hr post-surgery. In contrast, in all of the Bcl-2 transgenic mice examined, optic nerves regenerated robustly over long distances and reached their brain targets in 4 days after optic nerve crush. However, the majority of regenerating fibers, appearing to follow the existing optic tract and visual pathways, entered the visual targets that are ipsilateral to the nerve injury. Much less number of regenerating axons innervated their contralateral visual targets. To further investigate the mechanisms that lead to the ipsilateral target innervation by regenerating axons, we performed optic nerve crush followed immediately by contralateral eye enucleation. Four days after surgery, the regenerating fibers were found to avoid the optic pathway and be forced into the forebrain, entering the white matter of the cortex. Conclusion: Overexpression of Bcl-2 is sufficient to support the intrinsic growth mechanisms of retinal ganglion cell axons and enables robust optic nerve regeneration over long distances in vivo if the injury is incurred at 3 days after birth. However, the regenerating axons appear to follow the existing CNS pathways and innervate uninjured brain areas.
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