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Distinct pathways drive anterior hypoblast specification in the implanting human embryo.

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Weatherbee, Bailey AT  ORCID logo
Iwamoto-Stohl, Lisa K 
Barnikel, Zoe 


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.


Acknowledgements: The authors thank patients at CARE, Herts & Essex, Bourn Hall Fertility and King’s Fertility Clinics for their generous donations, as well as the embryologists and members of each clinic for facilitating donations. We thank G. Serapio-García for advice on Bayesian statistical analysis and the bioinformaticians and data scientists who made their code, packages and vignettes available. This work is supported by Wellcome Trust (207415/Z/17/Z) and Open Atlas and NOMIS awards to M.Z.-G. B.A.T.W. was supported by the Gates Cambridge Trust. C.W.G. was supported by a Leverhulme Trust Early Career Fellowship. L.K.I.-S. was supported by the Rosetrees Trust.

Funder: NOMIS Stiftung (NOMIS Foundation); doi:

Funder: Open Atlas

Funder: Gates Cambridge Trust; doi:

Funder: Leverhulme Trust; doi:

Funder: Rosetrees Trust; doi:


Pregnancy, Female, Humans, Germ Layers, Embryo, Mammalian, Embryonic Development, Signal Transduction, Embryo Implantation

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Nat Cell Biol

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Springer Science and Business Media LLC
Wellcome Trust (207415/C/17/Z)
Wellcome Trust (207415/Z/17/Z)
Open Atlas NOMIS Gates Cambridge Trust Leverhulme Trust Rosetrees Trust