In peripheral nerves, Schwann cells form myelin, which greatly accelerates axonal conduction. Myelination defects cause the symptoms of Charcot-Marie-Tooth disease and other peripheral neuropathies, but the mechanisms that regulate the formation of myelin remain unclear. Investigating the pathways that regulate Schwann cell myelination will lead to important advances in the understanding of peripheral nerve development and define mechanisms that can enhance remyelination after injury and in disease. The long-term goal of this project is to define the pathways that govern the formation of myelin in peripheral nerves. In the current funding period, we discovered that the orphan adhesion G protein coupled receptor (aGPCR) Gpr126 is essential for Schwann cells to initiate myelination. Like most adhesion GPCRs, the ligand that activates Gpr126 remains unknown. We have preliminary evidence that type IV collagen in the Schwann cell extracellular matrix binds Gpr126 and activates cAMP production in cultured cells expressing Gpr126. We also have preliminary evidence that purified type IV collagen stimulates cAMP production in purified rodent Schwann cells. We propose to test the hypothesis that type IV collagen acts as an endogenous activating ligand for Gpr126.
Our specific aims are (1) to analyze the action of type IV collagen on rodent Schwann cells, and determine if the response to collagen requires Gpr126;(2) to analyze the function of type IV collagen genes in Schwann cell myelination in vivo;and (3) to analyze the functional effects of a variant in Gpr126 that is linked to a severe neurological deficit in human. These experiments will define the signals that activate Gpr126 signaling and myelination, lead to new insights into the role of the extracellular matrix in regulating myelination, and test the function of a Gpr126 variant linked to severe neurological disease in human.

Public Health Relevance

The long-term goal of this research is to discover new regulators of Schwann cell myelination, which will lead to important fundamental advances in the understanding of peripheral nerve biology and provide new avenues toward therapies for peripheral neuropathies. In this project, will we test the hypothesis that type IV collagen in the Schwann cell extracellular matrix activates the Gpr126 signaling pathway, and also work to understand how a variant in GPR126 is involved in a severe neurological deficit in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS050223-10A1
Application #
8817076
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2004-08-02
Project End
2019-05-31
Budget Start
2014-08-01
Budget End
2015-05-31
Support Year
10
Fiscal Year
2014
Total Cost
$352,616
Indirect Cost
$133,866
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Campbell, Philip D; Shen, Kimberle; Sapio, Matthew R et al. (2014) Unique function of Kinesin Kif5A in localization of mitochondria in axons. J Neurosci 34:14717-32
Paavola, Kevin J; Sidik, Harwin; Zuchero, J Bradley et al. (2014) Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126. Sci Signal 7:ra76
Glenn, Thomas D; Talbot, William S (2013) Analysis of Gpr126 function defines distinct mechanisms controlling the initiation and maturation of myelin. Development 140:3167-75
Glenn, Thomas D; Talbot, William S (2013) Signals regulating myelination in peripheral nerves and the Schwann cell response to injury. Curr Opin Neurobiol 23:1041-8
Raphael, Alya R; Lyons, David A; Talbot, William S (2011) ErbB signaling has a role in radial sorting independent of Schwann cell number. Glia 59:1047-55
Monk, Kelly R; Oshima, Kazuo; Jors, Simone et al. (2011) Gpr126 is essential for peripheral nerve development and myelination in mammals. Development 138:2673-80
Monk, Kelly R; Talbot, William S (2009) Genetic dissection of myelinated axons in zebrafish. Curr Opin Neurobiol 19:486-90
Voas, Matthew G; Glenn, Thomas D; Raphael, Alya R et al. (2009) Schwann cells inhibit ectopic clustering of axonal sodium channels. J Neurosci 29:14408-14
Monk, Kelly R; Naylor, Stephen G; Glenn, Thomas D et al. (2009) A G protein-coupled receptor is essential for Schwann cells to initiate myelination. Science 325:1402-5
Voas, Matthew G; Lyons, David A; Naylor, Stephen G et al. (2007) alphaII-spectrin is essential for assembly of the nodes of Ranvier in myelinated axons. Curr Biol 17:562-8

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