Recording morphogen signals reveals origins of gastruloid symmetry breaking*

Aggregates of stem cells can break symmetry and self-organize the morphogenesis of embryo-like structures and gene expression patterns. How multicellular self-organization emerges from signaling interactions between stem cells is not well understood. It has been proposed that a reaction-diffusion Turing instability in Wnt signaling defines the posterior of the gastruloid, a simplified model which recapitulates aspects of anterior-posterior (A-P) patterning. However, distinguishing candidate mechanisms of polarization requires linking early cell states to future cell positions along the A-P axis. Here we use synthetic “signal-recording” gene circuits to study symmetry breaking in the gastruloid during the evolution of a polarized Wnt pattern from an initially homogeneous state. We find that cell sorting, rather than a long-range Turing mechanism, rearranges early domains of Wnt activity into a single pole which defines the gastruloid axis. We also trace the emergence of Wnt domains to earlier heterogeneity in Nodal activity, even before Wnt activity is detectable. Our study defines a mechanism through which aggregates of stem cells can form a patterning axis even in the absence of external spatial cues.