Mechanisms of ventral body wall closure

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The abdomen (belly) of a baby is formed in the womb by the wrapping of the internal organs, first by a thin layer of so-called mesoderm and ectoderm ("primary body wall") and then by muscle and connective tissue ("secondary body wall"). How the secondary wall replaces the primary is not understood, but a snug fit is maintained throughout the process because the internal organs are growing rapidly at the same time. About one in 2000 babies are born with a defect in the abdominal wall, which most often presents clinically as a hole in the abdomen through which parts of the gut and sometimes the liver protrude (herniate). The causes of abdominal wall defects are also not well understood, in part because the basic embryology involved has not been studied in a detailed quantitative way. In the proposed project, we will use the mouse embryo, in which abdominal wall closure is very similar to that in humans, as a model to understand the details of growth, reshaping and physical forces that must work together to enable the secondary body wall to form. We will first make a 'growth atlas' of the abdominal wall to determine how the entire process coordinates replacement of the primary wall by the secondary wall while containing the internal organs. To link the anatomical changes with our understanding of cell biology, we will look in fixed specimens at the cells that make up all the tissues to see how the growth and re-shaping are achieved by cell multiplication, rearrangement, and size change, and take pieces of living embryonic tissue in which cells are fluorescently labelled so that we can microscopically observe these cell behaviours individually. We will compare embryos from healthy mice with those from mouse mutants known to have frequent abdominal closure defects to see which cellular processes are abnormal so as to cause abdominal defects. Finally, we will test the idea that the abdominal wall growth is triggered and coordinated by mechanical tension, exerted by primary body wall narrowing and pulling on the secondary body wall and by expansion of the growing internal organs. To do this, we will map tension across the growing abdominal wall and see if it correlates in space or time with cell proliferation and make small incisions to relieve local tension, investigating whether this reduces local proliferation. We will also investigate a molecular signalling pathway, known as Yap/Taz, that is known in other situations to stimulate cell proliferation in response to tension, and ask if it is present, active, and necessary for abdominal wall growth. Together the investigations in this project will provide an integrated understanding of abdominal wall closure, establishing the basic biology and elucidating ways in which birth defects might occur.