The long-range goal of this project is to elucidate the role of extracellular matrix (ECM) in the development of the peripheral nervous system. The proposed work is based on the hypothesis that developmental switches in ECM composition and structure help determine the functional activities of axons and Schwann cells. Before the onset of myelination, proliferating and migrating Schwann cells synthesize and assemble a fibrillar ECM that contains, among other components, fibronectin and a nerve-specific isoform of collagen type V (collagen typeVsc). The distinguishing feature of this collagen is a Schwann cell-specific collagen chain that was identified on the basis of its high affinity binding to syndecan-3, a transmembrane heparan sulfate proteoglycan expressed in the developing nervous system. Syndecans function as ECM receptors and regulate cell adhesion, migration, and cytoskeletal organization. In vitro, many ECM molecules, including most collagens, promote migration of Schwann cells and axonal outgrowth. Collagen type Vsc, in contrast, has the unusual property of inhibiting migration of dorsal root ganglion axons. This suggests that a function of collagen type Vsc is to regulate nerve fiber outgrowth during development, by restricting lateral migration of axons. This idea is supported by cell culture studies, which demonstrate collagen type Vsc promotes fasciculation of axons in primary co-cultures of embryonic nerve cells and Schwann cells. The proposed experiments address the function of collagen type Vsc and the role of syndecan-3 in regulating Schwann cell and axonal cytoskeletal organization and migration. This work will explore the hypothesis that cells interact with collagen type Vsc through multiple receptors that cooperate to produce the observed effects on cell activity.
The specific aims are to identify functional domains of collagen type Vsc and characterize their Schwann cell and neuronal receptors, to investigate the function of collagen type Vsc in vivo, and to elucidate the function of the syndecan-3 cytoplasmic domain. The information obtained from these experiments will provide important new information on the development and function of the peripheral nervous system.
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