The Adhesion GPCR GPR126 Has Distinct, Domain-Dependent Functions in Schwann Cell Development Mediated by Interaction with Laminin-211

• The Gpr126-NTF functions in radial sorting independent of the CTF
• Laminin-211 interacts with a novel laminin-binding domain in the GPR126-NTF
• Laminin-211 can suppress or promote GPR126-mediated Gs signaling
• SC development and myelination depend on bimodal GPR126-Laminin-211 interactions

SummaryMyelin ensheathes axons to allow rapid propagation of action potentials and proper nervous system function. In the peripheral nervous system, Schwann cells (SCs) radially sort axons into a 1:1 relationship before wrapping an axonal segment to form myelin. SC myelination requires the adhesion G protein-coupled receptor GPR126, which undergoes autoproteolytic cleavage into an N-terminal fragment (NTF) and a seven-transmembrane-containing C-terminal fragment (CTF). Here we show that GPR126 has domain-specific functions in SC development whereby the NTF is necessary and sufficient for axon sorting, whereas the CTF promotes wrapping through cAMP elevation. These biphasic roles of GPR126 are governed by interactions with Laminin-211, which we define as a novel ligand for GPR126 that modulates receptor signaling via a tethered agonist. Our work suggests a model in which Laminin-211 mediates GPR126-induced cAMP levels to control early and late stages of SC development.