Temporal BMP4 effects on mouse embryonic and extraembryonic development

Ron Hadas, Hernan Rubinstein, Markus Mittnenzweig, Yoav Mayshar, Raz Ben-Yair, Saifeng Cheng, Alejandro Aguilera-Castrejon, Netta Reines, Ayelet-Hashahar Orenbuch, Aviezer Lifshitz, Dong-Yuan Chen, Michael B. Elowitz, Magdalena Zernicka-Goetz, Jacob H. Hanna, Amos Tanay () and Yonatan Stelzer ()
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Ron Hadas: Weizmann Institute of Science
Hernan Rubinstein: Weizmann Institute of Science
Markus Mittnenzweig: Weizmann Institute of Science
Yoav Mayshar: Weizmann Institute of Science
Raz Ben-Yair: Weizmann Institute of Science
Saifeng Cheng: Weizmann Institute of Science
Alejandro Aguilera-Castrejon: Weizmann Institute of Science
Netta Reines: Weizmann Institute of Science
Ayelet-Hashahar Orenbuch: Weizmann Institute of Science
Aviezer Lifshitz: Weizmann Institute of Science
Dong-Yuan Chen: California Institute of Technology
Michael B. Elowitz: California Institute of Technology
Magdalena Zernicka-Goetz: California Institute of Technology
Jacob H. Hanna: Weizmann Institute of Science
Amos Tanay: Weizmann Institute of Science
Yonatan Stelzer: Weizmann Institute of Science

Nature, 2024, vol. 634, issue 8034, 652-661

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07937-5

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