Mesp1 controls the speed, polarity, and directionality of cardiovascular progenitor migration

During embryonic development, Mesp1 marks the earliest cardiovascular progenitors (CPs) and promotes their specification, epithelial-mesenchymal transition (EMT), and cardiovascular differentiation. However, Mesp1 deletion in mice does not impair initial CP specification and early cardiac differentiation but induces cardiac malformations thought to arise from a defect of CP migration. Using inducible gain-of-function experiments during embryonic stem cell differentiation, we found that Mesp2, its closest homolog, was as efficient as Mesp1 at promoting CP specification, EMT, and cardiovascular differentiation. However, only Mesp1 stimulated polarity and directional cell migration through a cell-autonomous mechanism. Transcriptional analysis and chromatin immunoprecipitation experiments revealed that Mesp1 and Mesp2 activate common target genes that promote CP specification and differentiation. We identified two direct Mesp1 target genes, Prickle1 and RasGRP3, that are strongly induced by Mesp1 and not by Mesp2 and that control the polarity and the speed of cell migration. Altogether, our results identify the molecular interface controlled by Mesp1 that links CP specification and cell migration.