The role of schwann cells in peripheral nerve development in zebrafish

Myelin is a specialized sheath that insulates axons and allows for the rapid conduction of action potentials. In the peripheral nervous system, myelin is made by glial cells called Schwann cells. Whereas Schwann cells have received attention mainly because of their role in generating myelin, they play many other important roles. Using the posterior lateral line nerve in zebrafish, I have investigated two aspects of Schwann cell development. First, I demonstrate a new role for Schwann cells in repositioning peripheral nerves. Second, I find that ErbB signaling and Schwann cell proliferation are required during radial sorting, a process during which Schwann cells change their interactions with axons and reorganize the structure of the nerve itself. The posterior lateral line nerve is a prominent peripheral nerve in zebrafish that innervates sensory organs called neuromasts. I find that the posterior lateral line nerve initially grows out within the epidermis but is then rapidly transitioned across the basement membrane into the subepidermal space. Schwann cells are required for this process; in three different mutants that lack Schwann cells, the nerve is consistently mislocalized to the epidermis. This mislocalization results in significant disorganization of the nerve that worsens over time. When wildtype Schwann cells are transplanted into mutants lacking Schwann cells the position of the nerve is rescued. These results provide evidence that moving the posterior lateral line nerve out of the epidermis, across the basement membrane, protects the nerve from the migration of its targets. Before Schwann cells can make myelin around an axon, they must go through several developmental steps. Immediately after Schwann cells and axons have completed their migration, each Schwann cell associates with many axons. In order for myelination to proceed, however, a Schwann cell must associate with only a single axon. This transition, termed radial sorting, results in significant reorganization of the nerve. Neuregulin signaling from axons through ErbB receptors on Schwann cells controls many aspects of Schwann cell development and in mammals both Neuregulin/ErbB signaling and Schwann cell proliferation have been implicated in radial sorting. This prompted me to investigate whether ErbB signaling was required to regulate Schwann cell proliferation during radial sorting. To test this I took advantage of the zebrafish model system and used small molecule inhibitors to inhibit either ErbB signaling or proliferation at the time when radial sorting is beginning. I find that ErbB signaling and Schwann cell proliferation are critical for radial sorting. ErbB signaling was also required for Schwann cells to extend processes into the axon bundle, while proliferation was not. Therefore, I propose that ErbB signaling is directly required during radial sorting to regulate Schwann cell process extension, in addition to the previously established role of ErbB signaling in stimulating Schwann cell proliferation.