HEPARAN SULFATE PROTEOGLYCANS IN NEURAL DEVELOPMENT

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Recent studies have documented important roles for heparan sulfate proteoglycans (HSPGs) in the control of nervous system development. HSPGs are proposed to regulate processes as diverse as neural cell differentiation, cell adhesion, and the pathogenesis of human diseases such as Alzheimer's Disease (AD). Recent studies from our laboratories have shown that agrin and collagen XVIII are two extracellular matrix (ECM) HSPGs of nervous tissue. Agrin is an extracellular matrix protein identified and named based on its involvement in the aggregation of acetylcholine receptors (AChRs) during synaptogenesis at the neuromuscular junction (NMJ). Emerging evidence indicates that agrin's function is not limited to its role in synaptogenesis, as the majority of agrin expression occurs in the developing central nervous system, especially in developing axonal tracts. The studies outlined in this proposal are aimed at understanding how agrin functions in brain development and aging by interacting with specific ECM molecules in the nervous system. The proposed studies will also analyze the functional significance of collagen XVIII in nervous system development and angiogenesis. The specific goals of this proposal are: 1) To analyze the role of agrin in ECM function in the developing nervous system. These experiments will include studies that will test the hypothesis that interactions between agrin and ECM proteins are necessary for cell interactions in the developing nervous system, and that agrin plays a role in the formation of the ECM during nervous system development. 2) To examine the expression of agrin, and ECM proteins that bind to agrin, in normal and Alzheimer's Disease brain. The rationale for these studies is based on the hypothesis that HSPGs may play a crucial role in the formation of amyloid plaques in AD. 3) To characterize chicken collagen XVIII and to understand its functional significance in the developing nervous system. Our recent molecular studies have demonstrated that collagen XVIII is an ECM HSPG of the nervous system, in particular the PNS. In the present proposal, we will complete the molecular cloning of chicken collagen XVIII and begin to assess the functional significance of collagen XVIII. In particular, we will examine the role of this HSPG as an anti-angiogenic molecule. These studies are of interest since the C-terminal domain of collagen XVIII is endostatin, a known anti-angiogenic molecule that is also anti-tumorigenic. Finally, we will analyze the role of collagen XVIII in blood vessel formation during CNS development.