Myc-driven endogenous cell competition in the early mammalian embryo

Abstract

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.

Mechanisms and mechanics of cell competition in epithelia

“…This paper also suggests that intrinsic variation in endogenous MYC levels could contribute to selection of the fittest cells 95 . A representation of expected stresses and strains in and around a clone of cells that grow faster than the surrounding tissue.…”

Competition between human cells by entosis

“…While the identity of the engulfing cells and whether engulfment itself mediates competition in Drosophila are controversial, we clearly show that neighboring cell-mediated engulfment and killing occur in mixed populations of human cells. Other mechanisms of competition between mammalian cells have been demonstrated, including the differential extrusion of cells of mixed genotypes from monolayer cultures [9,10], competition between cells of the early embryo [36][37][38], and competition between hematopoietic progenitors driven by differences in p53 activity [39,40]. Perhaps diverse competition mechanisms reflect a stringent requirement for homeostasis in different contexts within various tissue types of metazoan organisms during development and adulthood.…”

p53 pathway is involved in cell competition during mouse embryogenesis

“…p53 is known to play a significant role in influencing the metabolic and redox profiles of cells (34), which might be associated with the cells' competitive status. In addition, p53 has been shown to be able to antagonize c-Myc (35), whose level is critical in determining cell fitness during cell competition in both Drosophila and mice (18,36). Thus, it is possible that the relative levels and activities of p53 and c-Myc play instructive roles in the competition of cells in a heterotypic environment.…”