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The epiblast is the mammalian embryonic tissue that contains the pluripotent stem cells that generate the whole embryo. We have established a method for inducing functional genetic mosaics in the mouse. Using this system, here we show that induction of a mosaic imbalance of Myc expression in the epiblast provokes the expansion of cells with higher Myc levels through the apoptotic elimination of cells with lower levels, without disrupting development. In contrast, homogeneous shifts in Myc levels did not affect epiblast cell viability, indicating that the observed competition results from comparison of relative Myc levels between epiblast cells. During normal development we found that Myc levels are intrinsically heterogeneous among epiblast cells, and that endogenous cell competition refines the epiblast cell population through the elimination of cells with low relative Myc levels. These results show that natural cell competition in the early mammalian embryo contributes to the selection of the epiblast cell pool.
Multicellular organisms have evolved tissue homeostasis mechanisms to ensure life-long fitness of their organs and systems. Among these mechanisms, those that regulate the elimination of unwanted cells are fundamental for tissue development and homeostasis1. Whereas overtly damaged or hyperproliferative cells usually trigger well-characterized cell-autonomous apoptotic pathways2, mechanisms that survey viable cell fitness to optimize a tissue's cell composition are less well under- stood. A candidate mechanism is the phenomenon of cell competition, first described in Drosophila3. Studies in flies have shown that the cells of growing organs are able to compare their fitness with that of neighbour- ing cells, and the less-fit but otherwise viable cells are eliminated (out- competed) when confronted with a fitter cell population (competitor)3-8. Cell competition for survival is an active process because, in addition to a contribution from differential proliferation9, it is executed through the apoptotic elimination of the less-fit population by cell non-autonomous mechanisms10. Cell parameters that trigger competition in flies include differences in protein synthesis capacity, growth factor receptivity and the expression level of rfMyc3-5·10, a major activator of cell anabolism. Super- competition is a variant of cell competition in which cells moderately overexpressing dMyc outcompete wild-type (WT) cells5. The replace- ment of cell populations through cell competition is phenotypically silent, because the competitor cells mostly conform to size-control mechanisms3-5. This process is potentially...