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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS079445-08
Application #
9732883
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Morris, Jill A
Project Start
2018-07-01
Project End
2021-04-30
Budget Start
2018-07-01
Budget End
2019-04-30
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Neurosciences
Type
Overall Medical
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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