Distinct modes of cell competition shape mammalian tissue morphogenesis

Cell competition (CC)—the sensing and elimination of less fit “loser” cells by neighbouring “winner” cells—was first described in Drosophila. Although proposed as a selection mechanism to optimize tissue and organ development, its evolutionary generality remains unclear. Here, by employing live-imaging, lineage-tracing, single cell transcriptomics and genetics, we unearth two intriguing CC mechanisms that sequentially shape and maintain stratified tissue architecture during mouse skin development. Early in embryonic epidermis, winner progenitors within the single-layered epithelium kill and clear neighbouring losers by engulfment. Upon stratification and skin barrier formation, the basal layer instead expels losers through a homeostatic upward flux of differentiating progeny. This CC switch is physiologically relevant, as when it is perturbed, so too is barrier formation. Our findings establish CC as a selective force to optimize function of a vertebrate tissue, but also illuminate how a tissue dynamically adjusts its CC strategies to preserve fitness as it encounters increased architectural complexity during morphogenesis. Overall design: Single cell RNA sequencing experiments were performed on wildtype and/or Mycn+/- primary murine epidermal cells isolated from two embryonic time points (E12.5 and E17.5).