The developing placenta, which in mice originates through the extraembryonic ectoderm (ExE), is essential for mammalian embryonic development. Yet unbiased characterization of the differentiation dynamics of the ExE and its interactions 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 three-way perturbation approach to target signalling 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 and chorion progenitors. Early BMP4 signalling from chorion progenitors is required for proper differentiation of uncommitted ectoplacental cone cells and later for their specification towards trophoblast giant cells. We also find biphasic regulation by BMP4 in the embryo. The early ExE-originating BMP4 signal is necessary for proper mesoendoderm bifurcation and for allantois and primordial germ cell specification. However, commencing at embryonic day 7.5, embryo-derived BMP4 restricts the primordial germ cell pool size by favouring differentiation of their extraembryonic mesoderm precursors towards an allantois fate. ExE and embryonic tissues are therefore entangled in time, space and signalling axes, highlighting the importance of their integrated understanding and modelling in vivo and in vitro.

小鼠发育中的胎盘起源于胚外外胚层 （ExE），对哺乳动物胚胎发育至关重要。然而，对 ExE 的分化动力学及其与胚胎本身的相互作用的公正表征仍然不完整。在这里，我们开发了一个小鼠原肠胚形成的时间单细胞模型，该模型绘制了胚胎和胚外谱系中的连续和平行分化。这与三向扰动方法相匹配，以靶向来自胚胎本身、单独 ExE 或两者兼而有之的信号传导。我们表明 ExE 规范涉及未定型的外胎盘锥细胞和绒毛膜祖细胞的早期空间和转录分叉。来自绒毛膜祖细胞的早期 BMP4 信号传导是未定型外胎盘锥细胞正确分化所必需的，后来是它们向滋养层巨细胞的规范所必需的。我们还发现 BMP4 在胚胎中具有双相调节作用。早期 ExE 起源的 BMP4 信号对于适当的中胚层分叉以及尿囊和原始生殖细胞规格是必需的。然而，从胚胎第 7.5 天开始，胚胎来源的 BMP4 通过有利于其胚外中胚层前体分化为尿囊命运来限制原始生殖细胞池的大小。因此，ExE 和胚胎组织在时间、空间和信号轴上纠缠在一起，突出了它们在体内和体外综合理解和建模的重要性。