Myelin is a layer of insulation that covers neuronal axon projections in the vertebrate nervous system. In the peripheral nervous system (PNS), Schwann cells (SCs) radially sort axons into a 1:1 relationship and then iteratively wrap axonal segments to form myelin. Myelin ensures that nerve impulses travel quickly and efficiently, ultimately allowing for the entire nervous system to function properly. Disruptions to the myelin sheath in disease (e.g., numerous peripheral neuropathies) or after injury lead to devastating symptoms, and significant morbidity. Moreover, myelin damage can lead to permanent neuron loss. Currently, no treatments exist to prevent demyelination or to hasten remyelination, and there is therefore a pressing need to develop therapies that address these issues. To this end, we must learn more about the mechanisms that govern SC development and myelination. We previously discovered that the adhesion G protein-coupled receptor (aGPCR) Gpr126 is essential for SC radial sorting and myelination, although the mechanisms by which Gpr126 controls these processes are only beginning to be understood. GPCRs are excellent drug targets, representing at least one-third of all approved drugs; thus, aGPCRs are extremely attractive therapeutic targets to stimulate remyelination in humans with myelin disease or injury. Interestingly, we have recently determined that Gpr56, an aGPCR related to Gpr126 is also required during SC radial sorting in development and myelin maintenance in adulthood. In addition to Gpr126 and Gpr56, we have determined that four other aGPCRs are expressed in SCs, though their functions are unknown. In this proposal, we seek to define the aGPCR-mediated SC developmental program. We will: (1) Determine how Gpr126 controls radial sorting; (2) Define the autonomy, downstream signaling, and ligands of Gpr56 in SCs; (3) Test if the four novel SC-expressed aGPCRs are required for PNS development, myelination, and/or myelin maintenance. These experiments will greatly strengthen our understanding of SC and aGPCR biology and may lay the foundation for future therapeutics that stimulate myelin repair in humans.
Lack of robust remyelination represents a major barrier in the recovery of neurological function in disease or after injury in many nervous system disorders. Here, we propose to determine how members of the adhesion G protein-coupled receptor class control myelin development and homeostasis. These studies can lay the foundation to help define new strategies to stimulate remyelination in the injured and diseased human nervous system.
| Giera, Stefanie; Luo, Rong; Ying, Yanqin et al. (2018) Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells. Elife 7: |
| Ackerman, Sarah D; Luo, Rong; Poitelon, Yannick et al. (2018) GPR56/ADGRG1 regulates development and maintenance of peripheral myelin. J Exp Med 215:941-961 |
| D'Rozario, M; Monk, K R; Petersen, S C (2017) Analysis of myelinated axon formation in zebrafish. Methods Cell Biol 138:383-414 |
| Herbert, Amy L; Monk, Kelly R (2017) Advances in myelinating glial cell development. Curr Opin Neurobiol 42:53-60 |
| Mogha, Amit; Harty, Breanne L; Carlin, Dan et al. (2016) Gpr126/Adgrg6 Has Schwann Cell Autonomous and Nonautonomous Functions in Peripheral Nerve Injury and Repair. J Neurosci 36:12351-12367 |
| Mogha, Amit; D'Rozario, Mitchell; Monk, Kelly R (2016) G Protein-Coupled Receptors in Myelinating Glia. Trends Pharmacol Sci 37:977-987 |
| Sigoillot, Séverine M; Monk, Kelly R; Piao, Xianhua et al. (2016) Adhesion GPCRs as Novel Actors in Neural and Glial Cell Functions: From Synaptogenesis to Myelination. Handb Exp Pharmacol 234:275-298 |
| Scholz, Nicole; Monk, Kelly R; Kittel, Robert J et al. (2016) Adhesion GPCRs as a Putative Class of Metabotropic Mechanosensors. Handb Exp Pharmacol 234:221-247 |
| Küffer, Alexander; Lakkaraju, Asvin K K; Mogha, Amit et al. (2016) The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6. Nature 536:464-8 |
| Salzman, Gabriel S; Ackerman, Sarah D; Ding, Chen et al. (2016) Structural Basis for Regulation of GPR56/ADGRG1 by Its Alternatively Spliced Extracellular Domains. Neuron 91:1292-1304 |
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