The research in our laboratory is focused on two major topics: (1) describing the molecular mechanisms that guide cell migration, and (2) elucidating fibroblast growth factor (FGF) receptor-mediated signal transduction pathways. We have developed genetic systems in the nematode Caenorhabditis elegans to identify the molecular components that are important for these processes, and use genetic, molecular biological, immunohistochemical, and biochemical approaches to analyze how these components function in a developing organism. We have also begun computational approaches to model the genotype-phenotype relationship.
Cell migration is crucial for normal metazoan development. To gain a better understanding of some of the mechanisms that guide migrating cells to their final destinations, we study the migrations of a pair of cells known as sex myoblasts (SMs) in C. elegans hermaphrodites. The SMs give rise to a set of muscles that are essential for egg laying, allowing us to identify SM migration mutants by their inability to lay eggs.
Mutations in two genes, egl-15 and egl-17 (EGg Laying defective), alter the normal interaction between the gonad and the SMs, changing the attraction to a repulsion. These genes encode a fibroblast growth factor (FGF) receptor tyrosine kinase and its putative ligand, respectively. Current experiments are aimed at trying to relate this FGF signaling pathway to the normal attractive signal that guides the migrating SMs to their precise final positions.
The EGL-15 FGF receptor tyrosine kinase is required for other processes in C. elegans besides SM migration guidance. Using suppressor screens, we have identified other components that interact with this FGF receptor in mediating the signaling events essential for these processes. One of these, CLR-1 (CLeaR), functions to attenuate signaling through EGL-15 and encodes a receptor tyrosine phosphatase. The molecular identity of the CLR-1 phosphatase is consisent with its genetic role in negatively regulating a process controlled by the egl-15-encoded kinase. Three additional genes have been identified that behave genetically as mediators or activators of egl-15 and are thus candidates for being other ligands or the downstream components of FGF receptor signaling pathways. One of these, sem-5, encodes an SH2/SH3-containing adaptor protein that is also involved in a highly conserved Ras signaling pathway and is functionally interchangeable with its human homolog GRB2. The other two genes are currently being molecularly characterized. The high degree of evolutionary conservation of these pathways indicates that these studies will serve as an important basis for the understanding of FGF receptor signaling mechanisms in general.