Schwann cells (SCs) are myelinating glial cells which are derived from neural crest cells in the peripheral nervous system (PNS). SCs surround axons of motor neurons with myelin sheath for rapid saltatory conduction, prevention from damage of risk factors and support of axonal functions. In addition, these cells are essential for development of motor nerve and perineurial glia which is a compo- nent of blood-nerve-barrier during early development. Although SCs have multiple roles for the normal development and function of motor nerves, molecular mechanisms and cellular interactions regulating formation of normal motor nerve fascicles are poorly understood. Spinal motor neurons are classified into two types, which are early-born primary motor neurons (PMNs) and late- born secondary motor neurons (SMNs) in zebrafish. We found that axons of PMNs are myelinated by SCs, whereas axons of SMNs are unmyelinated and surrounded by motor exit point glia (MEP) glia in the PNS of zebrafish larvae. In addition, we found that unmyeli- nated SMNs form neuromuscular junctions to both fast and slow muscles, whereas myelinated PMNs do only fast muscles. By using genetic manipulations and chemical inhibitor, we showed that Neuregulin1 (Nrg1) type3-ErbB2/3 signaling pathway is required for the development of SCs, including recruitment and myelina- tion. Finally, We showed that perineurial glia form ensheathment onto both myelinated PMNs and unmyelinated SMNs by interacting with SCs and MEP glia, respectively. Altogether, our data indicate that Nrg1type3-ErbB2/3 signaling regulates selective myelination of primary motor nerves and development of MEP glia, which are required for perineurium formation in the zebrafish PNS.
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