Myelin is a layer of insulation that covers neuronal projections called axons in the vertebrate nervous system. In the peripheral nervous system, specialized cells called Schwann cells spiral themselves around axons to form the myelin sheath. 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 (like multiple sclerosis or peripheral neuropathy) or after injury (like spinal cord trauma) lead to devastating symptoms, significant morbidity, and myelin loss can lead to permanent neuron loss, and ultimately, paralysis. 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 myelination, myelin maintenance, and remyelination. We discovered that the orphan G protein-coupled receptor, Gpr126, is an essential component of the incompletely understood axon-Schwann cell signaling nexus that controls myelination. In Gpr126 mutant mice, Schwann cells associate with axons, but fail to spiral their membranes to generate the myelin sheath. G protein-coupled receptors are excellent drug targets, representing at least one-third of all approved drugs;thus, Gpr126 represents an extremely attractive potential target to stimulate remyelination in humans with myelin disease or injury. We therefore propose to dissect the mechanisms by which Gpr126 controls myelination and to determine if Gpr126 is required for myelin homeostasis or remyelination after injury. These studies encompass our broad goals to define the mechanisms that form, maintain, and regenerate myelinated axons in the vertebrate nervous system. In the first aim, we will define the signaling pathway downstream of Gpr126 activation by performing biochemical analyses on Gpr126 mutant tissue and cells. In the second aim, we will test the hypothesis that Gpr126 is required autonomously in Schwann cells for myelination. We will employ conditional mouse mutants to delete Gpr126 specifically in Schwann cells or in neurons, and we will perform immunohistochemical and ultrastructural analyses to determine the consequences of cell type specific loss. In this aim, we will also define the developmental window of Gpr126 requirement by temporally deleting Gpr126 in developing embryonic and perinatal transgenic mice. In the third aim, we will define the roles of Gpr126 in adult peripheral nerve. Specifically, we will determine if Gpr126 is required for myelin maintenance, demyelination, and/or remyelination after nerve injury by temporally deleting Gpr126 in mature nerve and in injured mature nerve. Together, these experiments will define the mechanisms by which Gpr126 controls myelination, will elucidate if Gpr126 is required for remyelination in adult nerve, and may lay the foundation for future therapeutics that stimulate myelin repair in humans.
Lack of robust remyelination represents one of the major barriers to recovery of neurological functions in disease or following injury in many disorders of the nervous system. Here, we propose to determine how Gpr126 controls myelination during development and to elucidate whether Gpr126 is required for myelin maintenance and remyelination in adult nerves. These studies will help to 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 |
| 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 |
| Ackerman, Sarah D; Monk, Kelly R (2016) The scales and tales of myelination: using zebrafish and mouse to study myelinating glia. Brain Res 1641:79-91 |
| 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 |
Showing the most recent 10 out of 24 publications
