Schwann cells selectively myelinate primary motor axons via neuregulin-ErbB signaling

Spinal motor neurons project their axons out of the spinal cord via the motor exit point (MEP) and regulate their target muscle fibers for diverse behaviors. Several populations of glial cells including Schwann cells, MEP glia, and perineurial glia are tightly associated with spinal motor axons in nerve fascicles. Zebrafish have two types of spinal motor neurons, primary motor neurons (PMNs) and secondary motor neurons (SMNs). PMNs are implicated in the rapid response, whereas SMNs are implicated in normal and slow movements. However, the precise mechanisms mediating the distinct functions of PMNs and SMNs in zebrafish are unclear. In this study, we found that PMNs were myelinated by MEP glia and Schwann cells, whereas SMNs remained unmyelinated at the examined stages. Immunohistochemical analysis revealed that myelinated PMNs solely innervated fast muscle through a distributed neuromuscular junction (NMJ), whereas unmyelinated SMNs innervated both fast and slow muscle through distributed and myoseptal NMJs, respectively, indicating that myelinated PMNs could provide rapid responses for startle and escape movements, while unmyelinated SMNs regulated normal, slow movement. Further, we demonstrate that neuregulin 1 (Nrg1) type III-ErbB signaling provides a key instructive signal that determines the myelination of primary motor axons by MEP glia and Schwann cells. Perineurial glia ensheathed unmyelinated secondary motor axons and myelinated primary motor nerves. Ensheathment required interaction with both MEP glia and Schwann cells. Collectively, these data suggest that primary and secondary motor neurons contribute to the regulation of movement in zebrafish with distinct patterns of myelination.