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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078542-04
Application #
7825431
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Haynes, Susan R
Project Start
2007-08-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$294,882
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Kadam, Snehalata; Ghosh, Srimoyee; Stathopoulos, Angelike (2012) Synchronous and symmetric migration of Drosophila caudal visceral mesoderm cells requires dual input by two FGF ligands. Development 139:699-708
McMahon, Amy; Reeves, Gregory T; Supatto, Willy et al. (2010) Mesoderm migration in Drosophila is a multi-step process requiring FGF signaling and integrin activity. Development 137:2167-75
Tulin, Sarah; Stathopoulos, Angelike (2010) Extending the family table: Insights from beyond vertebrates into the regulation of embryonic development by FGFs. Birth Defects Res C Embryo Today 90:214-27
Tulin, Sarah; Stathopoulos, Angelike (2010) Analysis of Thisbe and Pyramus functional domains reveals evidence for cleavage of Drosophila FGFs. BMC Dev Biol 10:83
Kadam, Snehalata; McMahon, Amy; Tzou, Phoebe et al. (2009) FGF ligands in Drosophila have distinct activities required to support cell migration and differentiation. Development 136:739-47
Supatto, Willy; McMahon, Amy; Fraser, Scott E et al. (2009) Quantitative imaging of collective cell migration during Drosophila gastrulation: multiphoton microscopy and computational analysis. Nat Protoc 4:1397-412
McMahon, Amy; Supatto, Willy; Fraser, Scott E et al. (2008) Dynamic analyses of Drosophila gastrulation provide insights into collective cell migration. Science 322:1546-50