Epithelial Sheet Dynamics during Primitive Streak Formation as Active Matter

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An important goal of the study of development of higher animals including humans is understanding gastrulation. Gastrulation is a critical stage in early embryonic development where the main body plan of the embryo is laid down and the main body axes emerge. It involves large-scale, long-range cell movements during which cells of the three tissue layers, the ectoderm, the mesoderm and endoderm take up their correct positions in the embryo. The endoderm is located innermost in the embryo and adult, lining the digestive tract and associated glands. It is surrounded by the mesoderm that will give rise to the muscles and the skeleton, which is in turn covered by the outmost layer, the ectoderm, which will form the epidermis and the nervous system. Defects in cell movements during gastrulation result in severe cases in death and in less severe cases form the basis of many birth defects.The cellular processes and chemical signalling underlying gastrulation in higher vertebrates (such as humans) are experimentally studied in so-called model systems, especially chick and mouse embryos. The chick embryo has the advantage that development takes place outside the mother and is therefore easily experimentally accessible. It is also flat and translucent which helps observation of cell movement during gastrulation. Gastrulation in chick embryos greatly resembles gastrulation in humans, which means that findings can be extrapolated to human development. During very early stages development the chick embryo consists of two concentric disks of tissue sitting on top of the yolk; the inner, one cell layer thick, ring will form the embryo proper. Cells in a sickle shaped domain on one side of this epiblast disc will differentiate into the mesoderm and endoderm. During gastrulation this sickle shaped domain of mesendoderm cells deforms into a stripe of tissue extending from one edge of the embryo through the central midline; the structure is known as the primitive streak. The central cells of the primitive streak then move inwards and away from this site of ingression to form the inner mesodermal and endodermal layers of the embryo.In this project we will study gastrulation in the chick embryo using two complementary approaches. First, we use experiments to follow the mechanical and chemical cell-to-cell signalling in the developing embryo at a cell-level detail. In order to do so we have developed and built a novel type of microscope, a light-sheet fluorescence microscope, that allows us to see almost all the cells in the embryo (50,000-200,000) in a special chick strain in which the cell membranes of all cells are marked with a green fluorescent protein. We study how different cell behaviours such as division, shape changes and motion are coordinated to generate these tissues and which chemical and mechanical cell-cell signalling mechanisms control them. Second, we build a computational model based on active, interacting cells using concepts from the physics of collective motion and use it to understand cell flow both at the local and the full embryo scale. Our study of the interplay between cell-cell signalling, cell differentiation, proliferation and migration is not only important to the community of researchers whose interest is focused on embryogenesis but will also be of great importance to scientists whose research is centred on processes such as wound healing, tissue repair and regeneration. Furthermore, in order to progress with the proposed research we will develop several new mathematical and computational techniques which are expected to be of great value for further mathematical investigation of other biological and biomedical/engineering problems.