Developmental roadmap of primordial germ cells in humans and pigs

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Studying the development of the gametes, the cells that make egg and sperm, in mammals is important for understanding the basis of animal development and evolution. It also has important applications in biotechnology, assisted reproduction, species conservation and regenerative medicine.We and others have shown that germ cell precursors, the primordial germ cells (PGCs), emerge in the posterior region of early embryos in large mammals (e.g. pigs and non-human primates), and that key genes that control development of germ cell precursors is conserved in these species. Although the period when PGC form is known, the features of the cells that respond to inducing signals is unknown. In this project we will test the hypothesis that cells with a unique molecular signature localized in the posterior end of the embryo can respond to specific signals to form germ cell precursors. We will carry out experiments to establish the genetic and epigenetic profile of PGC precursors in an embryo, and functional experiments using pig epiblast stem cells and human embryonic stem cells to identify key master regulators of germ cell development. The results of the project will help us gain a detailed understanding of how PGCs are induced from a pool of progenitor cells. This will be achieved by mapping the genetic and epigenetic signatures of pig PGCs and their precursors to build an atlas of their developmental progression, and by performing experiments using stem cells to identify role of a key master gene (SOX17) regulating this process. Intriguingly, the master regulator SOX17 is involved in the program of germ cells and gut progenitors. Here we will determine how this protein can elicit a differential response to inducing signals produced in the surrounding tissues to initiate two different programs of differentiation in an embryo. These comprehensive investigations will provide detailed molecular understanding of the formation of the PGCs in a large mammal for the first time. This new knowledge will be important for establishing improved methodologies for the study of human PGC development from stem cells in humans and livestock species. Development of new technologies that allow the generation of gametes in the laboratory will have broad applications for understanding the causes of infertility in humans through modelling of gametogenesis, for gaining better understanding of the origin of germ cell tumours, and for assisted reproduction in livestock. This project addresses questions of strategic relevance in the BBSRC remit, such as lifelong health and wellbeing. We anticipate that the outcomes of the current project will contribute to the academic and clinical advance in the areas of regenerative medicine and global food security.