Schwann cell migration and myelination in zebrafish peripheral nerves

The nervous system connects cells throughout the body to coordinate actions and transmit signals. Critical to the nervous system are the neurons that extend axons to their targets and the glial cells that interact with these axons. Oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system wrap axons to make the myelin sheath. Myelin is critical for enhancing the speed of action potentials as well as providing support to axons. Myelin was a critical adaptation that has allowed vertebrates to increase in size, precision of movement, and complexity. Insults to myelin cause devastating diseases, and a better understanding of the normal development of myelinating glia is necessary for improving treatment of human neuropathies. In this dissertation I investigate both well-known and novel signaling pathways and their roles in Schwann cell migration and myelination in zebrafish peripheral nerves. Before making myelin, Schwann cells must migrate along and cover the surface of a bundle of axons. Here, I demonstrate that Neuregulin 1 type III (Nrg 1 type III) is required in neurons to signal through ErbB receptors in Schwann cells for Schwann cell migration along the posterior lateral line nerve, a mechanosensory nerve. Further, ectopic expression of this signal in all neurons is sufficient to attract peripheral Schwann cells into the spinal cord. There appears to be distinct regulation of Schwann cell migration in different nerves of the peripheral nervous system, as migration of Schwann cells in motor nerves requires ErbB receptors but not the Nrg 1 type III ligand. Nrg1 type III does, however, control myelination in both sensory and motor nerves. Schwann cell migration is not only important to properly localize Schwann cells, but also to localize the lateral line nerve itself, which begins in the epidermis but then transitions across a basement membrane to the subepidermal space. As they migrate, Schwann cells degrade the basement membrane beneath the skin, which allows the nerve to transition out of the epidermis, and then rebuild the basement membrane after the nerve has been repositioned and protected from the disorganization that otherwise would take place if it remained in the epidermis. Finally, through analysis of a mutation that was found in a forward genetic screen for genes essential in myelination, I also identify a novel regulator of Schwann cell myelination. Together this work elucidates new roles of known genes in Schwann cell and nerve development and also identifies a novel gene required for peripheral myelination.