Axonal outgrowth is guided by molecular cues deposited in trails, or spatial gradients, on the extracellular matrix. Growth cones navigating these pathways must express the appropriate receptors in the proper sequence. Thus, the final patterning of axon tracts reflects genetic programs that control the expression of directional cues and neuronal receptors. The major goals are to 1) identify the cellular substrata that support axonal outgrowth, 2) characterize the spatial patterning of directional cues that guide axonal outgrowth, 3) identify the neuronal receptors and their temporal programming, and 4) learn how localized receptor activation steers growth cone direction. Using the genetic model Caenorhabditis elegans, the applicant has identified three genes whose products guide axonal outgrowth, unc-6, unc-5, and unc-40. UNC-6 is a laminin-related matrix protein secreted by epidermal cells (neuroglia), that, like its vertebrate homologues the netrins, guides the dorsal and ventral migration of axons. UNC-5, a transmembrane receptor for UNC-6, guides dorsal migration, and UNC-40, a DCC homologue, is necessary for ventral migration. In the proposed experiments, the localization of UNC-6, UNC-5, and UNC-40, and the dependence of their pattern on other genotypes will be studied. A gene that interacts with unc-6, adn-2, and a related gene adn-1, will be molecularly characterized. The experimental plan also investigates how a navigational program intrinsic to motile cells, the wingless signal transduction pathway, controls the polarity of guidance receptor expression during migrations. Disheveled, which is a key player in the wingless pathway is encoded by the mig-5 gene in C. elegans. Genetic interactions between UNC-40 and the wingless pathway will be studied by examining mig-5 expression in unc-40 mutants. UNC-6/netrin, UNC-40/DCC, and the wingless pathway are phyletically ancient and highly conserved in structure. Therefore, analysis of their roles in regulating axon and cell migration during normal and mutant development may aid the rational design of molecular therapies for the repopulation of axon tracts severed by injury or destroyed by disease.
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