Synchronization of Placenta and Embryonic Development Underlies Mouse Gastrulation

Throughout embryogenesis, the extra-embryonic ectoderm (ExE) and its progenies play a pivotal role in constructing and maintaining a functional placenta, directing gastrulation and cell specification. Yet, despite its unquestionable importance, our knowledge of ExE differentiation and its cross-talk with the embryo proper remains incomplete. To address this, we developed a temporal model of mouse gastrulation by analyzing transcriptomes of single cells derived from individual embryos from implantation to somitogenesis. The resulting model allows studying parallel differentiation in both embryonic and extra-embryonic lineages while accounting for prominent morphological transformations. Harnessing this powerful platform, we next sought to dissect the functional roles of BMP4, a key signaling factor that displays complex inter-lineage and temporal expression patterns during gastrulation. To this end, we devised an experimental framework that allows separating temporal, inter-lineage, and cell-intrinsic effects following BMP4 manipulation in vivo. Analyzing single cells derived from more than 50 individual embryos in which BMP4 was eliminated either in the germline or exclusively in the ExE lineage or the embryo proper, revealed a specific requirement for primordial germ cell specification, differentiation of the mesoderm and extra-embryonic mesoderm lineages, and formation of primary embryonic blood. The latter resulted in adverse developmental outcomes validated by smFISH and immunofluorescence of histological sections. Together, the new unified model for mouse gastrulation portrays the ExE-embryo interface and offers a quantitative platform for investigating the major signaling events orchestrating mammalian development.