Grant: Operating Grant

During the embryonic development of humans and other animals, many cells undertake relatively long-range migrations to populate new tissues. Amazingly, the paths taken by the migrating cells are largely the same in different individuals of the same species. This happens because secreted molecular cues interact with receptors on the migrating cells and guide them to their proper destination. Many inherited human diseases result from mutant genes that normally govern cell migration. In addition, the spread of metastatic tumor cells, which are responsible for more than half of cancer-related deaths, is invariably dependent on many of the same proteins that facilitate guided cell migration. A thorough understanding of the genes required for guided cell migration is therefore essential if we are to detect migration-related diseases and develop new therapies to treat them. In my lab, we use a nematode worm called C. elegans to study the genes required for guided migration. Studies have repeatedly shown that worm genes often have similar functions in other animals, including humans. We recently discovered that motor neurons secrete a previously uncharacterized gene product called MADD-4 to attract muscle cell extensions. MADD-4 is a member of a protein family that exists in many animals, including humans, but is poorly understood. We suspect that MADD-4 interacts with a muscle-expressed protein complex called UNC-40-EVA-1 to direct the muscle cell extensions. Given that very few guidance cues are known, the discovery of a novel cue is exciting. In this grant application, we propose to: (1) Investigate how MADD-4 interacts with the receptor complex, and (2) Identify and characterize other gene products that work with MADD-4 to guide the migration of cells and cell extensions. Given our unique reagents and the power of our model system, we are in an excellent position to provide important insight into this well-conserved, but poorly understood protein family.