Understanding the mechanisms of aneuploid cell elimination during early mammalian development

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During early development errors in cell division causes the daughter cells to have either fewer or extra numbers of chromosomes. This condition is called aneuploidy and is highly detrimental to embryogenesis. During development, aneuploid cells are normally removed from the embryo by the quality control mechanisms that ensure tissue fitness. When this is not possible aneuploidy causes miscarriage. However, in spite of aneuploidy being the leading cause of spontaneous pregnancy loss in humans, we still know surprisingly little about the consequences of chromosomal abnormalities during embryonic development.In this proposal we aim to identify what happens to aneuploid cells during early mammalian development. For this we will do three things:First, we will analyse which are the most important properties of aneuploid cells during early embryo development. To achieve this, we will use the mouse embryo as our model system as its early development recapitulates many features of human development. Using this system, we will artificially induce aneuploidy in cells and embryos and analyse what types of stress pathways are activated in these cells. Once the specific stress pathways that are induced by aneuploidy are identified, these will manipulated to test if activation reproduces the adverse effects of aneuploidy. We will also test if inhibiting these stresses prevents aneuploid cell elimination in the embryo.The second thing that we will do to study what happens to aneuploid cells during development is to analyse what signals are activated by aneuploidy induced stress and cause the death of aneuploid cells and embryos. Our previous work has identified the mTOR pathway, that is a key regulator of cell growth, as important for the elimination of abnormal cells during embryonic development. Here we will test the importance of the mTOR pathway for the elimination of aneuploid cells by asking how its repression prevents aneuploid cell propagation.The third thing that we will do to study aneuploidy during embryogenesis is to analyse exactly when aneuploid cells are eliminated during embryo development. For this we will study the levels of aneuploidy at different stages of mouse embryogenesis.Together we anticipate that our studies will provide a comprehensive overview of what the fate of aneuploidy is in the embryo and what are the adverse effects of aneuploidy.