Axon guidance along the dorsoventral axis of Caenorhabditis elegans

grantor: University of TorontoAxon guidance along the dorsoventral axes of animals belonging to diverse phyla involves secreted netrin/UNC-6 laminin related guidance cues and the UNC-5 and DCC/UNC-40 receptor families. Genetic studies in 'C. elegans ' reveal that both UNC-5 and UNC-40 are required to repel motile cells or axons away from UNC-6, while UNC-40 is required to attract motile cells or axons toward ventral sources of UNC-6. The UNC-5 guidance receptor, in response to the UNC-6/netrin path cue, orients growing axons in a dorsal direction along the epidermis of ' C. elegans'. When ectopically expressed in the touch receptor neurons, which normally extend ventrally or longitudinally, UNC-5 is able to reorient their axons toward the dorsal side in an UNC-6 dependent manner. This property forms the basis of a genetic screen to identify other mutations that, like ' unc-6' mutations, suppress 'unc-5'-induced growth cone guidance. These mutations may identify new components required for pioneer axon guidance by 'unc-5'. In this study, I describe eight genes that are required for ectopic 'unc-5'-induced growth cone steering. Four are the previously known axon guidance genes 'unc-6, unc-40, unc-34 ', and 'unc-44', and four are the novel genes: ' unc-129, seu-1, seu-2', and 'seu-3'. I propose that some or all of these genes may function in a developmentally important ' unc-5' signaling pathway. Mutations in 'unc-129' cause dorsal axon guidance defects that are similar to those exhibited by mutations in 'unc-5, unc-6', and 'unc-40'. I show that 'unc-129' encodes a novel member of the transforming growth factor-ß (TGF-ß) family of secreted signaling molecules and is expressed in a restricted pattern that includes motor neurons and dorsal body wall muscle. By further restricting expression to either motor neurons or to muscle, I found that expression in muscle is required for axon guidance. Ectopic expression studies indicate that asymmetric expression of 'unc-129', with expression in dorsal, but not ventral body wall muscle, is essential for axon guidance. The work discussed here provides the first functional evidence that a TGF-ß is involved in a phylogenetically conserved axon guidance mechanism.Ph.D