Role of FGF Signaling in Controlling Cell Movements During Drosophila Development

California Institute Of Technology, Pasadena CA

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Abstract

DESCRIPTION (provided by applicant): Fibroblast growth factor (FGF) signaling impacts a number of different cellular functions important for supporting embryonic development. FGF ligands are polypeptide growth factors that trigger tyrosine kinase activity associated with the intracellular domains of their receptors, and thereby elicit signaling responses within cells. Differential expression of genes encoding ligands and receptors is one mechanism by which signaling pathway activation is regulated; while another is that only a subset of all possible ligand-receptor interactions are functional. We have found that only three of six possible FGF-FGFR interactions are acting in Drosophila melanogaster: Pyramus and Thisbe FGF ligands each support activation of the FGFR Heartless, while only the FGF ligand Branchless supports activation of the Breathless FGFR. In vertebrates, specificity of ligand-receptor protein interactions also certainly limits functional FGF-FGFR combinations, nevertheless, the vertebrate system remains quite complex with over 120 combinations possible. We contend that the simpler Drosophila model system is particularly well-suited to advance understanding of the molecular mechanism by which FGF signaling acts during development and, in particular, in the coordination of collective cell movement. In Drosophila embryos, signaling through the Heartless FGFR is important for controlling mesoderm spreading during gastrulation and also, subsequently, for migration of caudal visceral mesoderm cells in the embryo; these important mesoderm cell movements, required to support cardial and visceral mesoderm development, are disorganized in the absence of FGF signaling. In addition, we have also acquired evidence using the Drosophila system that FGF ligand choice, levels, and cleavage-state can all affect FGFR-dependent outputs. Collectively, our results support the view that FGF ligands that act concurrently to activate the same receptor are not redundant, contrary to the generally accepted belief in the vertebrate field, and instead suggest that FGF ligands fulfill distinct roles in the Drosophila embryo. We plan to take advantage of the simpler Drosophila model system to uncover additional novel insights into how this important signaling pathway is regulated and, in particular, to explore a previously underappreciated link between FGF signaling and the regulation of cell adhesion. The study has three aims: (1) To test the idea that FGF signaling supports cell movement by regulating cells' adhesivity; (2) To obtain insight into the role of FGF signaling in supporting cell movement by conducting live in vivo imaging studies; (3) To investigate how FGF activity is regulated by proteolytic cleavage and/or differences in ligand diffusion range. This study in Drosophila will provide novel insight into regulation of FGF signaling, which is important as many diseases and dysplasias in humans relate to aberrant signaling through this pathway. Uncontrolled cell migration in humans can lead to detrimental effects on the heart and vasculature development as well as to metastasis. For all these reasons, understanding how coordinate cell migration is controlled by FGF signaling has the potential for far-reaching impact.