When Prince Charming is blinded by his fall from Rapunzel's tower, her tears of joy restore his vision. In reality, losing one's sight is a life-long sentence because the human optic nerve – like most of the mammalian nervous system – has a limited capacity for self-repair. Yet there are many examples in the animal kingdom of growth and reinnervation of the central nervous system following injury. For example, zebrafish experience full functional recovery from optic nerve damage in as little as 3 weeks! What's their secret? Certainly there are many, but a group headed by Lieve Moons at the University of Leuven, Belgium, recently unlocked one. Their study, published in the Journal of Comparative Neurology, describes how a group of restructuring enzymes called matrix metalloproteinases (MMPs) work together to help the retina re-communicate with the brain after optic nerve damage.
To regain sight after optic nerve damage, the sensory neurons of the retina must regrow their axons through the optic nerve and establish new connections with the optic tectum of the brain, where visual signals are integrated. Moons’ research team wanted to establish the timeline of MMP activity during this repair process. They began by crushing the optic nerves of anesthetized zebrafish with forceps and then allowed the fish to recover for up to 3 weeks. At defined times during this recovery period, the team looked at the expression changes of specific MMPs in the retinas of some of the injured fish using immunohistochemistry and western blots. They noted dynamic changes in the expressions of two particular MMPs, MMP-13a and MMP-2, in the retina during the first week of recovery when axon regrowth peaks and approximately 60% of the optic tectum is reinnervated.
To fully lift the veil on the role of MMPs in ‘un-blinding’ zebrafish, Moons’ team reasoned that if they blocked MMP activity during the first week of recovery, then retinal axons would fail to reinnervate the optic tectum. So, they repeated the optic nerve crushing experiment, but this time they injected the injured eyes with either saline or an MMP inhibitor to block MMP activity. One week later, Moons’ team applied biocytin – a chemical label that is taken up by the axons and travels to their terminals – to the optic nerve, thus allowing the team to figure out whether the axons have found their way to the optic tectum. When they checked the zebrafish brains, the team found far less biocytin in the optic tectums of fish given the MMP inhibitor compared with fish given saline. This means that MMPs are crucial for helping axons regrow during the first week after injury to the visual system. Perhaps Rapunzel's magic was merely a healthy dose of MMPs.
