| During the development of the nervous system, the processes of cell migration, axon guidance and synapse formation are critical for the generation of precise synaptic connections. Two families of cell adhesion molecules, integrins and cadherins, have been shown to have numerous and diverse roles in these fundamental processes. Integrins are heterodimeric cell adhesion receptors that mediate cell attachment to the extracellular matrix and to some cellular ligands. Integrins provide a physical link between the extracellular matrix and the actin cytoskeleton, and also act as signaling receptors that transduce bidirectional signals across the cell membrane. Cadherins are a diverse superfamily of transmembrane glycoproteins that contain variable numbers of cadherin repeats. The classical cadherins mediate calcium-dependent homophilic adhesion and are connected to the actin cytoskeleton through the catenins. Nonclassic members of the cadherin superfamily often lack catenin-binding sites and vary widely their genomic organization, protein structures, and presumably in their localization and function.; In this dissertation I discuss several aspects of integrin and cadherin function underlying cell migration and axon guidance. In Chapter Two, I examine how cellular context affects the ligand specificity of integrin receptors. When three different human cell lines are transfected with the identical rat al integrin cDNA, each cell type shows different ligand specificities that can be correlated with differences in glycosylation. These observations emphasize the importance of cellular context in modulating integrin function and regulating cell adhesion. In the Appendix, I discuss preliminary RNA interference experiments designed to screen for integrin-associated proteins involved in neuronal migration in C. elegans. Because INA-1 integrin function is required for proper neuronal migration in C. elegans, identifying potential integrin-associated partners in this process could help define the pathway by which integrins regulate neuronal migration. In Chapter Three, I show that fmi-1, which encodes the C. elegans homolog of the unusual cadherin Flamingo, is required for axon guidance and synapse formation in C. elegans. Studies in Drosophila and mammals also suggest that Flamingo family members may have a conserved role in regulating neuronal morphogenesis. This chapter describes the mapping, cloning, and initial characterization of fmi-1. |
