Intercellular exchange of Wnt ligands reduces cell population heterogeneity in embryogenesis

Abstract Wnt signaling is required to maintain bipotent progenitors for neural and paraxial mesoderm cells, the neuromesodermal progenitor (NMP) cells that reside in the epiblast and tailbud. Since epiblast/tailbud cells receive Wnt ligands produced by one another, this exchange may average out the heterogeneity of Wnt signaling levels among these cells. Here, we examined this possibility by replacing endogenous Wnt3a with a receptor-fused form that can activate signaling in producing cells, but not in neighboring cells. Mutant mouse embryos showed a unique phenotype in which maintenance of many NMP cells was impaired, although some cells persisted for long periods. The epiblast cell population of these embryos increased heterogeneity in Wnt signaling levels as embryogenesis progressed and were sensitive to retinoic acid, an endogenous antagonist of NMP maintenance. Thus, mutual intercellular exchange of Wnt ligands in the epiblast cell population reduces heterogeneity and achieves robustness to environmental stress.