Mosaic gastruloids reveal a temporal restriction for developmental cell competition

Abstract Selective elimination of suboptimal cells is critical for the developmental integrity of early mammalian embryogenesis. Cell competition is a non-autonomous quality control in which ‘winner’ cells outcompete viable but suboptimal ‘loser’ cells based on fitness differences. Here we investigate cell competition dynamics using mosaic mouse gastruloids, a 3D embryonic stem cell-based model of gastrulation. Introducing just two Trp53- deficient supercompetitor cells suffices to impair growth in neighbouring wild-type cells through mitochondrial apoptosis. Competition is tightly restricted to a developmental transition stage between primed pluripotency and early gastrulation and involves gene regulatory networks of pluripotency exit. Heterochronic gastruloids from developmental stage-shifted cells, EpiGastruloids, and dynamic p53-degrons reveal that both winners and losers must reside within this permissive stage, during which acute relative p53 protein levels determine competitive outcomes. These findings advance our understanding of cell fitness evaluation and establish gastruloids as a powerful 3D model for investigating developmental stage-specific cell competition in mammalian embryogenesis.