Cadherins modulate the self-organizing potential of pseudo-embryos

Embryonic stem cells can be instructed to form gastruloids, an efficient four-dimensional model for studying some aspects of post-implantation embryonic patterning, which undergo gastrulation-like processes, illustrating their robust self-organizing capacity to form embryo-like patterns. Here, we study the molecular and cellular mechanisms underlying this remarkable property and report that self-organization competence is associated with a cell-specific coordination of a cadherin switch. E-cadherin repression by Snai1 is indeed critical for this process, with Snai1 triggering the cell-specific pace of pluripotency exit, thus allowing a coordinated transition from E- to N-cadherin to occur. In contrast, we find that N-cadherin inactivation unleashes gastruloids' morphogenetic competence, for it leads to the formation of embryo-like structures with proper rostro-caudal somite patterning without requiring any addition of extracellular matrix. Altogether, this work establishes a molecular mechanism that integrates the exit from pluripotency and the pace of cell differentiation, leading to the self-organizing potential of gastruloids.