Distinct pathways drive anterior hypoblast specification in the implanting human embryo

Abstract

Development requires coordinated interactions between the epiblast, which generates the embryo proper; the trophectoderm, which generates the placenta; and the hypoblast, which forms both the anterior signalling centre and the yolk sac. These interactions remain poorly understood in human embryogenesis because mechanistic studies have only recently become possible. Here we examine signalling interactions post-implantation using human embryos and stem cell models of the epiblast and hypoblast. We find anterior hypoblast specification is NODAL dependent, as in the mouse. However, while BMP inhibits anterior signalling centre specification in the mouse, it is essential for its maintenance in human. We also find contrasting requirements for BMP in the naive pre-implantation epiblast of mouse and human embryos. Finally, we show that NOTCH signalling is important for human epiblast survival. Our findings of conserved and species-specific factors that drive these early stages of embryonic development highlight the strengths of comparative species studies.

Smad4 is essential for epiblast scaling and morphogenesis after implantation, but nonessential before implantation

“…However, a different antibody was used to detect pSMAD1/5/9 in preimplantation embryos in Reyes de Model et al (2015) . The source of antibody that was used to detect pSMAD1/5/9 in blastocysts in Graham et al (2014) was not described in detail, but a more recent study from the same lab reported absence of pSMAD1/5/9 in the blastocyst using the same antibody that we used ( Weatherbee et al, 2024 ). Ours is the only study to confirm pSMAD1/5/9 specificity in Bmp4 null blastocysts, providing strong evidence for antibody specificity.…”