Investigating the mechanisms controlling cell survival during the first steps of embryonic differentiation

In the mouse and human embryo the onset of differentiation is accompanied by a dramatic series of changes at the level of gene expression, epigenetics, signalling, and metabolism. During this period the epiblast becomes hypersensitive to death stimuli and defective cells are eliminated. Cell competition has been proposed as a quality control mechanism that compares cell fitness levels within a cell population and eliminates those cells that are less fit than their neighbours, whilst promoting the proliferation of the fitter cells. In Drosophila, the transcription factor dMyc plays a key role in cell competition. This thesis examines the role of c-Myc, the mouse dMyc homologue, in mammalian cell competition, and demonstrates that c-Myc is key determinant of cell fitness in a number of developmental contexts. We find that in mouse embryonic stem cells (ESCs), and early post-implantation embryos, defective cells decrease c-MYC expression and are eliminated by apoptosis specifically when surrounded by high-MYC expressing neighbours. We also find that defective cardiomyocytes have low c-MYC expression during cardiac regeneration. Furthermore, we show that over-expression of c-Myc in ESCs is sufficient to turn cells into super-competitors, therefore capable of eliminating their wild-type neighbours, and that loss of c-Myc during early post-implantation development leads to reduced embryo size. Together these results indicate that relative c-MYC levels determine the outcome of cell competition during mammalian embryogenesis. We have also analysed what triggers cell competition during early development. Metabolomic analysis of wild-type and defective ESCs revealed that upon differentiation (that triggers cell competition), defective ESCs have significantly lower levels of glycolysis, TCA cycle activity and amino-acid synthesis, indicating a lower metabolic activity. These differences in cell metabolism suggest that during early development cell competition is acting as a metabolic selector mechanism, and eliminating those cells that are less metabolically active.