This project will exploit the power of cellular and genetic approaches in zebrafish to illuminate the functions of new genes that are essential for Schwann cell development and myelination in the vertebrate nervous system. In the peripheral nervous system, Schwann cells form the myelin sheath that wraps axons and allows for the rapid transmission of action potentials. Disruption of myelin causes peripheral neuropathies, debilitating diseases that affect 1.5 million people in the United States. Gaps in the understanding of the signals that govern the formation of myelin have hindered the development of therapies for the repair of myelinated axons. In genetic screens for mutations that disrupt myelination, we identified 13 mutations in 10 different genes with specific functions in the development of myelinated axons. Cellular and molecular studies demonstrate that the mutations define genes that function at many steps of the development of myelinated axons, including glial fate specification, Schwann cell migration, organization of the nodes of Ranvier, transport of specific myelin mRNAs within myelinating glia, and commitment of Schwann cells to myelination. In this application, we focus on a group of genes that have key functions in Schwann cell development and myelination. (1) In previous studies, we have identified mutations in erbb2 and erbb3, genes that encode components of a heteromeric receptor for Neuregulin (Nrg) signals, and showed that ErbB signaling is essential for directed migration of Schwann cells. In the present application, we propose to identify the operative signals and determine how they direct Schwann cells as they migrate along axons of growing peripheral nerves. We propose to determine which Nrg isoforms guide Schwann cell migration, to determine where these signals are expressed in developing nerves, and to determine whether Nrg signals are sufficient to guide migrating Schwann cells to ectopic locations. (2) In recent work, we found that two of our mutations disrupt a novel transmembrane protein. We propose to determine whether the protein acts as a signal or a receptor, or both, and to test the hypothesis that the gene acts in neurons to instruct Schwann cells to initiate myelination. In addition, we will test the hypothesis that this new transmembrane protein triggers myelination by activating krox20 in Schwann cells. (3) Our preliminary studies show that the st64 gene, which we are working to identify by positional cloning, is required for Schwann cell myelination. Our characterization suggests that analysis of the st64 mutation will define the function of a novel gene with an essential role in Schwann cell development. We propose to define the cellular and biochemical functions of the st64 gene by phenotypic analysis of the mutants and molecular analysis of the mutated gene.

Public Health Relevance

Disruption of the myelin sheath causes peripheral neuropathies, debilitating diseases that affect 1.5 million people in the United States. The long-term goal of this project is to discover new genes with essential functions in myelin formation using the powerful genetic and cellular approaches available in the zebrafish. The discovery of new genes and the development of new animal models will be an important step toward myelin repair therapies for peripheral neuropathies and other diseases of myelin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050223-09
Application #
8479442
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2004-08-02
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$328,031
Indirect Cost
$121,159
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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