Regulation of the Rho GEF Pebble in Fibroblast Growth Factor dependent cell migration

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The capability of cells to move is a highly regulated process in the human body. Cells can send and received signals that enable them to change position in an organism in a controlled fashion. These signals act upon a machine within the cell called the cytoskeleton, which allows cells to propel themselves forward in an organism or upon a substrate. Defects in the regulation of cell migration are the cause of many severe human diseases and a plethora of congenital disorders. Therefore to investigate the molecular detail of the signals and their action in cell migration is of utmost importance for our understanding of human diseases and to develop treatments against them.Research on human cellular disease pathways is often hampered by the fact that we cannot do experiments with humans for obvious reasons. One possibility is to utilise diseased cells or tissues, but these are no longer in contact with the entire organism and thus only provided limited insight. Another possibility is the use of so called model organisms. As the principal genetic repertoire of all multicellular animals is surprisingly similar, we can use simple organisms to investigate human disease pathways. Our laboratory is using the fruit fly Drosophila melanogaster, which has been employed for over 100 year in biomedical research. The power of Drosophila lies in its ease to manipulate its genes by mutations and other modifications. Our previous research has identified a signalling pathway triggered by a Fibroblast Growth Factor that is responsible for the onset and the directionality of cell migration in the fly embryo. As very similar molecules exerts similar functions in human embryos, our research results are transferable to humans.To identify the molecules that are involved in the regulation of cell migration through Fibroblast Growth Factor signalling we have conducted large scale genetic experiments. These genetic screens found mutations in other genes, which we then showed to be important for the regulation of the cytoskeleton during cell migration. In this research project we plan to determine how this regulation occurs on the molecular level and how the growth factor can modify the activity and the localisation of an important regulator of the cytoskeleton. We expect that the results from this research will provide new opportunities for research in drug discovery projects to establish assays that can detect small compounds leading to novel treatments of diseases in which cell migration is abnormal.