The long-term objective of this proposal is to understand the molecular basis of signaling specificity by fibroblast growth factor receptors (FGFRs). Fibroblast growth factors (FGFs) initiate many different types of biological events, including cell proliferation, angiogenesis, differentiation, cell migration, and cell survival. While much work has been done to elucidate one key FGFR signaling pathway, we have only a rudimentary understanding of the mechanisms that confer specific outcomes to FGF triggered events. FGFs play important roles in human health and disease. FGFs are known to be involved in many important developmental and homeostatic events, and aberrant FGF signaling is responsible for a number of skeletal and craniofacial syndromes. Studies in model organisms have helped elucidate the function of FGFRs and the signaling pathways they utilize. This proposal seeks to extend this understanding by analyzing FGFR signaling specificity in the nematode Caenorhabditis elegans, a model system with tremendously reduced cellular and molecular complexity. C. elegans possesses a single FGFR (EGL-15) and two known FGFs (LET-756 and EGL-17) that mediate several distinct functions: (1) an essential function; (2) guidance of the migrating sex myoblasts (SMs); and (3) the inhibition of sex muscle differentiation. This proposal will focus on how the ligands, specificity determinants on the receptor, and different signal transduction components combine to generate specific biological outcomes of FGFR signaling. We will analyze the specificity determinants on EGL-15 by structure/function studies. We will identify other components required for specific EGL-15 functions by using genetic screens for modifiers of EGL-15-induced phenotypes and by two-hybrid screens for proteins that interact with the specificity determinants on EGL-15. In this way, we will gain a clearer understanding of how specific responses are elicited by the activation of FGF receptors.
|Lo, Te-Wen; Branda, Catherine S; Huang, Peng et al. (2008) Different isoforms of the C. elegans FGF receptor are required for attraction and repulsion of the migrating sex myoblasts. Dev Biol 318:268-75|