Cell-cell adhesion plays a central role in a variety of developmental events, particularly in the establishment of the nervous system. Moreover, recent studies indicate that alterations in the expression of cell adhesion molecules(CAMs) accompany a number of pathological states. Since our demonstration that the neural cell adhesion molecule, N-CAM, contains five segments resembling the structural domains of immunoglobulins and two other segments that are similar to the type III repeats of the substrate adhesion molecule fibronectin, these structural features have been found in other CAMs. The chicken molecules Nr-CAM, Ng-CAM, and neurofascin and the rodent proteins L1/NILE and ankyrin binding glycoprotein constitute a subfamily of such CAMs in the nervous system: each of these distinct cell surface proteins has six immunoglobulin-like domains and five fibronectin-like repeats, and they are similar to each other in amino acid sequence. Moreover all of these molecules are expressed on neurons and appear to be important in the outgrowth and fasciculation of neurites. This group of CAMs could thus provide a basis for establishing neuronal pathways. The goal of this project is to define the properties of this subfamily and its role in neural development using Nr-CAM as the paradigm. Nr-CAM binds neurons to each other and binds neurons to fibroblasts by different mechanisms. Each of these activities will be examined in detail and the binding regions localized in the linear structure of the molecule using chemical, molecular biological and cell biological techniques. Features in Nr-CAM that are shared by other proteins in the subfamily will be analyzed for their role in Nr-CAM function. cDNA screening methods will be used to identify new members of this subfamily and to estimate the size of this group of proteins. Together these studies should provide a basis for defining the activities of proteins that are important in the development of the nervous system, and that are likely to play critical roles in a variety of processes such as nerve regeneration and in neurological diseases.