Cooperative short- and long-range interactions enable robust symmetry breaking and axis formation

The establishment of the anterior-posterior (A-P) axis is the first symmetry-breaking event in mammalian development, transforming initially uniform cell populations into a polarized body plan. Gastruloids, aggregates of embryonic stem cells, recapitulate this transition by reproducibly forming a posterior primitive-streak-like pole. To investigate the underlying physical principles, we constructed a coarse-grained agent-based model representing two radially differentiated cell populations — outer/peripheral and inner/core — interacting via short-range adhesion/surface tension and optional long-range chemotaxis-like forces. Systematic exploration of this morphogenetic landscape revealed that adhesion alone cannot robustly generate a single axis, often leading to weak or unstable asymmetries. By contrast, introducing long-range attraction among peripheral cells markedly broadened the parameter space for robust symmetry breaking, yielding high morphological asymmetry with low cell loss. We further implement a minimal, modular gene regulatory network that partitions cells into outer vs. inner states and gates adhesion and peripheral long-range attraction, converting an inside-outside bias into a stable axis. To facilitate further exploration, we developed DevSim, a user-friendly platform for simulating coupled genetic-mechanical rules in multicellular systems. Our results suggest that cooperative short- and long-range interactions are necessary design principles for reliable A-P axis formation in gastruloids and provide a framework for dissecting and engineering self-organizing developmental systems.