Adhesion G Protein-Coupled Receptors in CNS Development and Regeneration

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Myelin is the multilamellar membrane generated by glial cells that insulates, nourishes and protects axons in the vertebrate nervous system. In the central nervous system (CNS), oligodendrocytes (OLs) form the myelin sheath. OL follow an orderly and distinct developmental pattern with stage-specific functions. OL precursor cell (OPC) proliferate. Pre-myelinating OL (pmOL) mediate initial axon ensheathment and myelinating OL (mOL) carry out iterative axon wraps. Our published work demonstrates that G protein-coupled receptor (GPCR) GPR56 regulates OPC proliferation by mediating a tripartite signaling between OPC GPR56, microglia-derived tissue transglutaminase, and matrix protein laminin-111. Intriguingly, single cell RNAseq data reveals that, within the OL lineage, GPR56 is expressed highest at the pmOL stage. Our unpublished data provide tantalizing evidence that (1) pmOL GPR56 is required for F-actin formation; (2) deleting Gpr56specifically in pmOLs results in reduced myelination of the corpus callosum (CC); and (3) pmOLs lacking Gpr56 were unable to form myelin in co-cultured Shiverer cerebellar slices. Taking these data all together, we hypothesize that GPR56 functions in pmOLs to regulate actin organization of the pre-myelinating OL process. This proposal is designed to test this hypothesis, thus establishing novel GPCR signaling pathway in pmOL F-actin polymerization and axon ensheathment. Our data will enhance the understanding of the basic biology of myelination and will potentially reveal a new target for therapeutics to promote repair in the wide spectrum of neurological diseases that implicate myelin damage.