Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

During animal development, many cells must migrate in specific directions to reach specific locations where they form organs and complex tissues like the nervous system. Faulty cell migrations underlie many human disorders. We want to identify and understand novel, previously unknown molecular mechanisms involved in cell migration so we can better treat or prevent such disorders. We do this by making mutations in genes that affect cell migration of a model organism (C. elegans) in which cell migrations are easily followed microscopically and using each mutation to identify the gene responsible for the defect, which we then then clone and sequence. The information gleaned from this allows us to determine the nature of the product (usually a specific protein with human homologs) encoded by the gene. Portions of many proteins share specific amino acid sequences (aka domains) that have known functions at a molecular level, so often we can tell from the presence of such domains in a protein of interest, how that protein works. We can also deduce from the kind of cell migrations defect in the mutant (e.g. the cell wanders or is misdirected and never reaches its destination, or it fails to stop migrating in the correct place, or stops before reaching it, etc.) what role that protein plays in the migration process and compare this to the effects of mutations in other migration genes. We have recently identified mutations in genes that cause wandering or misdirected migrations at a specific stage of a multi-stage migration process. The protein products of two such genes help build sugar chains on secreted proteins, so we are beginning for the first time to understand how these sugar chains on specific proteins affect cell migration. Another gene modulates a previously known key gene that functions to guide migrating cells in the developing human central nervous system, so our studies should clarify how this modulation occurs at a molecular level. This is curiosity driven research, however, we hope (as often happens) that the knowledge gleaned from this research will eventually be applicable to understanding and treating several human developmental disorders as well as the abnormal migration of cells that occurs in metastatic cancer.