Retinoic acid coordinates the orderly construction of the mammalian body in the anterior-to-posterior sequence

Abstract In vertebrate embryos, anterior structures are formed early during gastrulation, while the posterior body develops subsequently. This temporal anterior-to-posterior developmental sequence is a fundamental aspect of animal development. Recent studies have shown that discrete regulatory modules involving Nodal and Wnt signaling pathways, in conjunction with T-box factors Eomes and Brachyury (Tbxt), underlie the differential specification of anterior and posterior mesoderm. However, the mechanism governing the transition from anterior to posterior mesoderm development remains unclear. Our findings suggest that retinoic acid signaling regulates the anterior-to-posterior developmental transition. Using mouse embryonic stem cell-based gastruloids, we show that the preclusion of retinoic acid signaling drives anterior mesoderm development, whereas the mesoderm specified in the presence of retinoic acid acquires posterior identity. Our observations indicate that retinoic acid signaling modulates the Wnt pathway. We demonstrate that both Eomes and Tbxt are essential for suppressing the posterior fate. The negative regulation of Wnt signaling by these T-box factors is critical, along with the preclusion of retinoic acid signaling, to ensure orderly anterior-posterior developmental progression. We propose that the preclusion of retinoic acid signaling early during gastrulation is crucial to maintain low Wnt signal levels, thereby driving anterior mesoderm specification. Subsequently, the activation of retinoic acid signaling results in high Wnt conditions, facilitating a switch to posterior mesoderm development. Competing Interest Statement The authors have declared no competing interest. Footnotes The introduction and discussion sections have been revised to be more focused and easier to read. New results have been included in some of the figures.