Regulators of polarised protein and vesicle traffic in a genetic model of vessel formation

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Tube formation is central to the development of most organs. We examine the genetic basis of heart tube formation in the simplest genetic model organism that has a heart- Drosophila. Our objective is to determine the mechanisms of cell signaling and cell differentiation that underlie the formation of a tubular structure like a human blood vessel. As with vertebrates, the progenitors of the Drosophila heart, called cardioblasts, arise in the embryo from the most lateral of the mesoderm cells. They migrate as a group towards the midline where they meet their opposite partners and form a vessel, which matures into the heart and aorta. In both vertebrates and Drosophila, this is a major collective cell migration event, which entails coordinated movement, cell signaling and differentiation. All three processes are dependent upon detecting unidirectional (polarising) cues, which then instruct the cell to re-organise, with an asymmetrically organised internal skeleton and membrane. These events culminate in the formation of a vessel, with three molecularly different surfaces- luminal (inside), lateral (between vessel cells) and basal (outside) membrane domains. We have identified the major receptor, called Robo, that guides and polarises cardioblasts as they migrate to the midline. Robo is also required for the formation of a lumen. We know that Robo does not act alone, and we seek to identify the other signals. Employing tools unique to Drosophila, we will uncover how signals from Robo act to organise the transport of molecules and membrane to the luminal surface of the vessel. We will express proteins in heart cells only, that glow under the microscope, and allow us to follow molecular changes in the heart cells of living embryos. At the same time we can look at changes in cell behaviour, caused by mutations that affect polarity signals or molecule targeting machinery, to build a model of how signals outside the heart cell instruct the assembly of a tube. We have yet to discover the genetic factors that predispose us to congenital heart disease. This research will advance live imaging as an R&D technology, and will direct efforts to developing predictive factors in congenital heart disease.