A fundamental question in developmental biology concerns the mechanisms by which cells and tissues assume their proper forms and positions in a developing organism. Morphogenesis is typified by the developing nervous system, where neurons extend cellular processes called axons that make specific contacts with other neurons to form an axon scaffold upon which functional neuronal connections are made. How are axons guided to their targets in the nervous system? Recent studies have identified genes that encode "sensor" molecules, transmembrane receptor proteins on the surface of the axon that detect information about guidance. However, the genes and mechanisms involved in translating a guidance signal into a morphological change in axon structure, mediated by the cellular scaffolding, remain largely a mystery. Dr. Lundquist's research aims to identify and analyze genes involved in the mechanisms of translating axon guidance information into axon morphological change. A molecular-genetic approach utilizing the nematode worm Caenorhabditis elegans will be taken to characterize new genes involved in axon morphogenesis. To this end, the role of lip-1 in axon pathfinding and unc-115 function will be determined. Furthermore, Dr. Lundquist will initiate a genetic screen for new mutations that disrupt axon morphogenesis. Genes involved in the regulation of the actin cytoskeleton will be targeted by screening for mutations that synergize with mutations in the unc-115, a gene encoding a novel actin-binding protein that is active during axon morphogenesis. New genes defined by these mutations will be isolated to determine the nature of the genes' function in morphogenesis. These studies will be greatly aided by the completely known C. elegans genome sequence. Similar studies using C. elegans and the fruit fly Drosophila melanogaster have uncovered fundamental mechanisms of cellular function, including mechanisms of cell fate determination and cell signaling during development. The studies described here will identify new genes and mechanisms used by neurons to translate guidance information into axon morphological change. Indeed, the roles of these genes will most likely be conserved in tissues other than neurons and in organisms other than C. elegans. Therefore, these studies will elucidate fundamental aspects of cellular morphogenesis during development and provide insight into the processes by which the rather unformed single-celled embryo develops into a complex organism. By incorporating these research activities into classroom and laboratory teaching, Dr. Lundquist will provide many opportunities for undergraduate and graduate student training in modern molecular genetics and genomics as well as in the skills of critical thought.
