| Fibroblast growth factor (FGF) receptors are a class of receptor tyrosine kinases required for a wide variety of signal transduction processes in vertebrates. Abnormal FGF receptor signaling is associated with disease syndromes in humans, including Pfeiffer and Apert syndromes, characterized by craniofacial abnormalities. FGF receptors signal through a number of critical intracellular signaling adaptor proteins, including the FGF receptor substrate-2 (FRS2) family of signaling adaptor proteins, but the complexity of the mammalian FGFR signal transduction pathways makes in vivo pathway dissection difficult. In this thesis, I use two parallel approaches to examine the FGF receptor signaling pathway using the nematode C. elegans as a model.;The first of these parallel approaches is a candidate gene approach examining the function and significance of the C. elegans ortholog of a known mammalian FGF receptor signaling adaptor protein. I will argue that the C. elegans gene rog-1 encodes the sole ortholog of the vertebrate FRS2 family proteins. ROG-1 shares no phenotypic similarity with EGL-15 and has no apparent genetic or physical interactions with EGL-15, the C. elegans FGFR. However, ROG-1 does appear to function upstream of Ras and MAP kinase in the germ line, where it is required for the proper progression through meiosis.;Having ruled out the C. elegans FGFR as a partner for ROG-1 function, I used a forward genetic screen to look for genes that might intervene between EGL-15 and downstream signaling adaptor proteins. This screen, performed in a sensitized genetic background, identified four mutations in EGL-15 itself that appear to act as loss-of-function mutations. Through this screen I have identified and approximately mapped one mutation which identifies a novel X-linked EGL-15 signaling gene. |
