The long range goal of this project is to understand the role of extracellular matrix (ECM) in the development of the nervous system. The terminal differentiation of Schwann cells, which involves spreading on axonal membranes and myelin formation is strictly dependent upon contact with ECM. In vivo and in primary cell cultures this ECM is the basement membrane that is synthesized by the Schwann cells prior to and during the period of myelination. This proposal addresses 3 related aspects of this overall goal; namely, the structure, function and regulation of expression of cell surface heparan sulfate proteoglycans (HSPGs) of Schwann cells. Previous studies from our laboratory have shown that Schwann cells synthesize 2 distinct cell surface HSPGs that differ in their mode of association with the cell surface: a lipid anchored HSPG and an HSPG that is similar or identical to a previously identified epithelial transmembrane HSPG syndecan. Other experiments from our laboratory suggest that these HSPGs are involved in the interaction of Schwann cell with the basement membrane protein laminin. We propose to investigate by immunocytochemical methods the subcellular localization of these HSPGs in Schwann cells at various stages of differentiation in culture. We will also determine whether nerve cell or basement membrane contact, which are known to strongly influence Schwann cell behavior, affect the synthesis, distribution, or processing these HSPGs by Schwann cells. These experiments will utilize a combination of biochemical, immunological and molecular techniques. To examine the function of the cell surface HSPGs we will add specific antibodies to cultures of Schwann cells and nerve cells and observe their effects on the ability of the Schwann cells to assembly basement membrane de novo and to respond to exogenous basement membrane be spreading on and ensheathing and myelinating axons. We will also attempt to clone cDNA encoding the core protein of the lipid anchored Schwann cell HSPG. For these experiment a Schwann cell cDNA expression library will be screened with antibodies or oligonucleotides. Core protein sequences will be subcloned into the appropriate vectors for further analysis, such as DNA sequence determination.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology C Study Section (NEUC)
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Weis Center for Research-Geisinger Clinc
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Chernousov, Michael A; Rothblum, Katrina; Stahl, Richard C et al. (2006) Glypican-1 and alpha4(V) collagen are required for Schwann cell myelination. J Neurosci 26:508-17
Rothblum, Katrina; Stahl, Richard C; Carey, David J (2004) Constitutive release of alpha4 type V collagen N-terminal domain by Schwann cells and binding to cell surface and extracellular matrix heparan sulfate proteoglycans. J Biol Chem 279:51282-8
Chernousov, Michael A; Carey, David J (2003) alphaVbeta8 integrin is a Schwann cell receptor for fibrin. Exp Cell Res 291:514-24
Zhang, Xue-Qian; Qureshi, Anwer; Song, Jianliang et al. (2003) Phospholemman modulates Na+/Ca2+ exchange in adult rat cardiac myocytes. Am J Physiol Heart Circ Physiol 284:H225-33
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Chernousov, M A; Stahl, R C; Carey, D J (2001) Schwann cell type V collagen inhibits axonal outgrowth and promotes Schwann cell migration via distinct adhesive activities of the collagen and noncollagen domains. J Neurosci 21:6125-35
Chernousov, M A; Carey, D J (2000) Schwann cell extracellular matrix molecules and their receptors. Histol Histopathol 15:593-601
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Fuentealba, L; Carey, D J; Brandan, E (1999) Antisense inhibition of syndecan-3 expression during skeletal muscle differentiation accelerates myogenesis through a basic fibroblast growth factor-dependent mechanism. J Biol Chem 274:37876-84

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