The diverse functions of the vertebrate brain are made possible by its enormous complexity at the cellular level. It is imperative, therefore, that dynamic adhesions between neurons and glia that are involved in the development of these complex cellular patterns be understood at the molecular level. Cell surface molecules that mediate such cell-cell adhesions have recently been identified but their functions are still poorly understood. The long-term objective of this work is to understand the role of molecules that mediate adhesion between neurons and glia both in normal and aberrant brain development and function. A molecule (Ng-CAM) that is involved in neuron-glia cell adhesion has been identified on neurons. This glycoprotein has been purified and antibodies have been prepared that specifically recognize Ng-CAM and inhibit binding between neurons and glial cells. Ng-CAM, however, does not appear on glia, suggesting that another cell adhesion molecule that binds to Ng-CAM will be found on these cells.
The specific aims of this proposal are to evaluate the function of Ng-CAM in development, to identify the ligand for Ng-CAM on glia (Gn-CAM) and to understand in detail the mechanism of neuron-glia binding. Specific antibodies to Ng-CAM will be used to determine the distribution of Ng-CAM in vivo and to perturb critical developmental events that are dependent on neuron-glia interactions, such as neuron migration on glial fibers and the layering of cells in the retina. Gn-CAM will be isolated by selecting molecules that neutralize inhibition by anti-(glial cell) antibodies of neuron-glia cell adhesion, a modified form of the assay used to purify Ng-CAM. Alternatively, Gn-CAM will be isolated on the basis of its ability to bind to Ng-CAM. Specific antibodies to Gn-CAM will be prepared and used to determine its localization in tissues and to evaluate its role in neuron-glia adhesion by perturbation experiments. These studies will provide a better understanding of the role of neuron-glia cell adhesion molecules in normal brain function. Because the ratio of glial cells to neurons is higher in man than in any other species, they may also help to provide key insights into the molecular bases of specific neurological disorders, such as multiple sclerosis, muscular dystrophy, gliomas and Alzheimer's Syndrome.
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