Mechanisms of Peripheral Nerve Injury and Recovery in a Zebrafish Demyelination Model

PROJECT SUMMARY In the peripheral nervous system, axons innervate distant targets in an exquisitely patterned network for sensation and motor control. Schwann cells, the myelinating glia of the vertebrate peripheral nervous system, provide essential trophic support and enwrap axons to support rapid conduction of action potentials throughout the body. In demyelinating neuropathies such as Guillain-Barré Syndrome, peripheral myelin is broken down and cleared by mechanisms that are not fully characterized, with impaired remyelination by injured Schwann cells. Development of therapies to prevent demyelination and promote remyelination is hindered by an incomplete understanding of these processes, in part because there are few models that assess glial- specific injury and demyelination. The goal of this project is to characterize cellular and molecular mechanisms of Schwann cell demyelination and identify factors that promote peripheral remyelination. To accomplish this goal, we have developed a novel larval zebrafish model in which we can chemically induce Schwann cell demyelination to visualize nerve damage and repair over time, in living organisms. In the first aim, we will test the hypothesis that Schwann cell demyelination results in secondary axon damage, recruitment of macrophages, and expression of the transcription factor c-Jun in injured Schwann cells. In the second aim, we will test the hypothesis that Schwann cell remyelination is dependent upon both the transcription factor Mitf and axon health. We will also test small molecules for enhancement of remyelinating potential, which can serve as candidate therapeutics for demyelinating disorders in humans. Altogether, our study employs a novel and highly tunable system to manipulate Schwann cell- specific damage and repair in peripheral nerves. Our system permits visualization of myelin sheath breakdown and reformation at high resolution, in real time, using non-invasive fluorescent microscopy. Ultimately, this study will define key factors driving myelin dynamics in disease states, which improves our understanding of both Schwann cell biology and treatments for demyelinating disorders.