In animals, fibroblast growth factor (FGF) signaling is reiteratively used throughout development to control many different processes. Among other functions, FGF signaling regulates cell migration, differentiation, and cell survival. FGFs function as extracellular ligands for FGF receptors (FGFRs), which are receptor tyrosine kinases. Tight regulation of ligand expression is surely one mechanism that ensures specificity of FGF signaling through FGFRs, but our hypothesis is that additional specificity is imparted by the amino acid sequence of each FGF ligand. We recently identified two genes in Drosophila encoding FGF ligands Pyramus (Pyr) and Thisbe (Ths), bringing the total number of FGF ligands in this organism to three. Our previous analyses have determined that Pyr and Ths activate the FGFR Heartless (Ht!). We have chosen to study specificity of FGF signaling in the fruit fly for several reasons. First and foremost, we seek to understand how different FGF ligands function to control different biological responses by activation of the same FGFR. Do the functions of FGF ligands a reflect differences in protein sequence or differential expression of these two genes? Second, we are interested in the general question of how activation of the same FGFR results in different cellular outcomes. How does activation of the Htl FGFR control cell migration and cell differentiation and could this reflect activation by different ligands? Lastly, this analysis has the potential to explain why different mutations in the ligand-binding domain of human FGFR cause different diseases;the implication of these findings is that FGF ligands have distinct functions. 22 FGF and four FGFR genes are found in humans;this increased genetic complexity of vertebrate genomes makes it more difficult to analyze FGFR signaling even in genetically tractable models systems such as the mouse. Whereas only three FGF and two FGFR genes have been identified in the fruit fly, and therefore this system is a more tractable one. We have proposed four specific aims that will significantly advance the understanding of FGF signaling specificity using Drosophila as a model system: 1) Analysis of FGF signaling responses controlled by Pyr and Ths ligands. 2) Contribution of location and timing of ligand expression to specificity. 3) Characterization of different ways in which ligands signal through the FGFR. 4) Dissection of how Htl FGFR activation by Pyr and Ths controls cell movement.
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