CARBOHYDRATES AND LECTINS IN NEURAL DEVELOPMENT

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Cell-cell recognition mediated by cellular contact contributes to the formation of specific synaptic connectivity during neural development. Localization to the cell surface, inherent structural diversity and regulat expression are properties ascribed to the carbohydrate moieties of glycoconjugates that are also to be expected of cellular recognition molecules. For cell surface carbohydrates to mediate, cell-cell interaction however,, endogenous protein receptors (lectins) should exist that recognize and discriminate between oligosaccharide ligands. A novel Drosophila melanogaster protein, called "gliolectin", is such a lectin. Identified through adhesion-based expression cloning, gliolectin is expressed by a subset of the glial cells at the midline of the embryonic Drosophila nervous system. Gliolectin's spatial and temporal expression pattern positions it to mediate the glia/neural or glia/glial interactions at guide formation of embryonic axonal commissures. Alterations in gliolectin expression (partial loss-of-function mutations) disrupt axonal outgrowth early in development. To define gliolectin's role in axonal guidance, this proposal takes advantage of the potential for genetic and molecular analysi of function offered by studying development in Drosophila. Phenotypes associated with null mutations in the gliolectin gene, with ectopic- expression of gliolectin protein and with double mutants that combine gliolectin mutations with mutations in other genes active at the Drosophila midline will be characterized. Immuno-electron microscopic examination of gliolectin's normal expression pattern will indicate whether gliolectin lie at the interface between midline glial cells or between glia and axon, a distinction important for interpreting mutant phenotypes. Also, gliolectin' carbohydrate binding will be further characterized in vitro and in situ to define the degree to which binding specificity controls specificity in cellular recognition. These complementary genetic, ultrastructural and biochemical approaches will define gliolectin's function and place it in th context of other molecular activities suggested to guide axon outgrowth across the Drosophila midline. Conserved molecular expression and developmental function have suggested that the Drosophila ventral midline is analogous to the floorplate of the vertebrate neural tube. Therefore, th identification of a vertebrate gliolectin homologue will place a lectin at crucial crossing point for vertebrate commissural axon pathfinding. Elucidation of cellular recognition mechanisms in neural tissue, including carbohydrate-mediated interactions, is essential for realization of full functional regeneration following CNS injury.