Regulation of cell fate decisions during gastrulation in mammals

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Early embryonic loss during the first three weeks of development affects ~30% pregnancies. Most of these losses are a result of genetic abnormalities, which become manifested during early gastrulation, the period when the first embryonic lineages are specified. The process of gastrulation is not well understood in humans, but emerging in vitro models called "gastruloids", using stem cells, can recapitulate morphogenetic processes that help us understand the role of critical genes during development. Our laboratory has pioneered the use of these systems in multiple mammalian species (human, pig, cow) with the aim of developing better understanding of the evolutionary differences between mammals. We previously showed that humans and pigs share principles of pre-implantation development, such as the formation of a flat embryonic disc, which differs considerably from the egg cylinder of mice. In this project we will test the hypothesis that the mechanisms of gastrulation in flat disc embryos follow distinct gene regulation and morphogenetics. The focus of the analysis will be particularly centred around the emergence of mesoderm and endoderm lineages. A combination in vitro (stem cell/gastruloids culture and cell imaging), in vivo embryo manipulation (gene editing), single cell transcriptomics (bioinformatics) and mathematical modelling will be used to study the roles critical developmental genes and signalling pathways responsible for the segregation of these germ layers. The paradigms studied here using large mammalian embryos will be contrasted with results in mouse embryos. The new understanding will inform how human embryos allocate cells towards basic germ layers and will expand our understanding of specific genetic abnormalities that may cause pregnancy failure. The findings will also be of key importance for enhancing the differentiation methods of stem cells towards specific lineages with an impact in regenerative medicine.