Drosophila neuroglian is a member of the L1 subfamily of immunoglobulin-like cell adhesion molecules (Ig-CAMs) whose members include the neuroglian homolog human L1. These molecules are thought to be involved in critical processes of embryonic nervous system development such as cell adhesion, neurite growth, axon fasciculation and intercellular signaling. There is evidence of considerable conservation of function between neuroglian and human L1 since mutations in both Drosophila neuroglian and human L1 lead to motor neuron axonal pathfinding defects. Much of what we know about the function of these molecules has been inferred from cell culture studies. Expression of neuroglian on the surfaces of transfected cells in culture causes the cells to aggregate, demonstrating homophilic cell adhesion. Current evidence suggests that certain regions (domains) in the portion of the molecule located on the exterior of the cell are necessary for cell aggregation in culture conditions. The experiments described in this proposal will extend these findings from cultured cells to the living organism. A technique termed P-element mediated germ-line transformation will be used to examine the function of protein variants of neuroglian in living Drosophila. These studies will determine which of the extracellular domains of neuroglian that are involved in cell adhesion in culture also are involved in producing the sensory cell patterning defects and motor neuron pathfinding defects that occur in mutant embryos. These studies also will investigate the effects on nervous system development of the overexpression of neuroglian in neurons. Effects of the mutant forms of neuroglian on axon fasciculation will be evaluated to determine whether physical adhesion is a major function of neuroglian, and if it is, to determine whether or not the domains involved in cell adhesion in cultured cells are the determinants of adhesion in the living animal.
