Temporal effects of BMP4 on mouse embryonic and extraembryonic development

The developing placenta, originated in the mouse through the extra-embryonic ectoderm (ExE), is essential for mammalian embryonic development. Yet, unbiased characterization of ExE differentiation dynamics and interaction with the embryo proper remains incomplete. Here, we develop a temporal single-cell model of mouse gastrulation that maps continuous and parallel differentiation in embryonic and extraembryonic lineages. This is matched with a 3-way perturbation approach to target signaling from the embryo proper, the ExE alone, or both. We show that ExE specification involves early spatial and transcriptional bifurcation of uncommitted ectoplacental cone cells (EPCs) and chorion progenitors. Early BMP4 signaling from chorion progenitors is required for proper differentiation of uncommitted EPCs and later for their specification towards trophoblast giant cells. We also find bi-phasic regulation by BMP4 in the embryo. The early ExE-originating BMP4 signal is necessary for proper endo-mesoderm bifurcation, allantois, and primordial germ cells (PGCs) specification. However, commencing at E7.5, embryonic-derived BMP4 source restricts PGC pool size by favoring differentiation of their extraembryonic mesoderm precursors towards an allantois fate. ExE and embryonic tissues are therefore entangled in time, space, and signaling axes, highlighting the importance of their integrated understanding and modeling in vivo and in vitro.