Abstract
Mature myelin sheaths insulate axons to increase nerve conduction velocity and protect nerve fibers from stress and physical injury. In the peripheral nervous system, the myelin sheath is produced by Schwann cells. The guanine-nucleotide exchange factor cytohesin-2 activates the protein Arf6 to promote Schwann cell myelination. Here, we investigated the regulation of cytohesin-2 and found that the phosphorylation status of Tyr381 in cytohesin-2 is central to Schwann cell myelination. Knockin mice with a nonphosphorylatable Y381F mutation in cytohesin-2 exhibited reduced myelin thickness and decreased Arf6 activity in sciatic nerve tissue. In HEK293T cells, cytohesin-2 was dephosphorylated at Tyr381 by the protein tyrosine phosphatase PTP4A1, whereas phosphorylation at this site was maintained by interaction with the adaptor protein SH2B1. Schwann cell-specific knockdown of PTP4A1 in mice increased cytohesin-2 phosphorylation and myelin thickness. Conversely, Schwann cell-specific loss of SH2B1 resulted in reduced myelin thickness and decreased cytohesin-2 phosphorylation. Thus, a signaling unit centered on cytohesin-2-with SH2B1 as a positive regulator and PTP4A1 as a negative regulator-controls Schwann cell myelination in the peripheral nervous system.