Schwann cells (SCs) are the myelinating glia of the peripheral nervous system (PNS) that associate with and wrap around axons to form the insulating myelin sheath. During development, immature SCs select appropriately sized axons (a process termed radial sorting) and repeatedly wrap their membranes around their selected axon. The importance of SC myelin is best underscored in diseases in which SC dysfunction leads to peripheral neuropathies such as Charcot-Marie-Tooth Disease; importantly, defects in radial sorting are frequently observed in human PNS disease. Advances in identifying growth factors and signaling molecules expressed by SCs reveal the myriad roles of glial cells in the nervous system and their interaction with each other, neurons, and the surrounding extracellular matrix (ECM). We have previously identified the adhesion G protein-coupled receptor (aGPCR) GPR56/ADGRG1 as a critical regulator of PNS myelination. Loss of Gpr56 function in zebrafish and mouse mutants results in delayed radial sorting. Consistent with the ability of aGPCRs to transduce extracellular stimuli into intracellular signals, we demonstrate that GPR56 signals through RhoA to promote SC radial sorting prior to myelination. Despite delays during early development, radial sorting in Gpr56 mutants recovers with time. However, the mature myelin ultrastructure is disorganized and we observe increased outfoldings with age. In spite of these key functions, it is unclear what developmental cues activate GPR56 in the PNS. In other contexts, GPR56 has two known binding partners, the ECM proteins collagen III and tissue transglutaminase 2, and our efforts to define the roles of these potential GPR56 interactors in the PNS will be discussed. Interestingly, however, an unbiased proteomics screen has identified additional candidate binding partners for GPR56 in the PNS. Currently, we are using CRISPR/Cas9-mediated genome editing to generate zebrafish mutants for these candidate genes in order to define their role in radial sorting as well as perform genetic interaction studies to test whether these mutants enhance gpr56stl13/stl13 phenotype. Together, our studies define the role of GPR56 PNS development, and our work has important implications for human neuropathies and myelin diseases.