A temporal coordination between Nodal and Wnt signalling governs the emergence of the mammalian body plan

Nodal and Wnt signalling play an important role in the emergence of the mammalian body plan, primarily by orchestrating gastrulation and primitive streak formation. While the literature suggests that these pathways cooperate to build the primitive streak, their individual contributions remain poorly understood, largely due to pleiotropic effects observed when key pathway components are knocked out in mouse embryos. In this study, we used gastruloids - a non-integrated stem cell model of mammalian gastrulation - to dissect the roles of Wnt and Nodal signalling. We found that Wnt/β-catenin signalling drives a genetic program characteristic of the late primitive streak, promoting the development of posterior body structures in a time and dose-dependent manner. Conversely, Nodal signalling activates a distinct developmental module resembling the early primitive streak. By engineering gastruloids with elevated Nodal signalling, we demonstrate that the decreasing temporal gradient of Nodal activity in the mouse primitive streak likely plays a pivotal role in establishing the anterior body plan, with higher Nodal levels producing more anterior structures in a concentration-dependent manner. Our findings suggest that rather than cooperating, Nodal and Wnt signalling act antagonistically, initiating distinct developmental modules within the primitive streak. This antagonism is likely the core mechanism driving the early body plan in mammals. Additionally, our results also lead to the suggestion that the gastruloid system models the primitive streak and reveals its self-organizing potential.