Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst

Claire S. Simon, Afshan McCarthy, Laura Woods, Desislava Staneva, Martin Proks, Nazmus Salehin, Georgia Lea, Qiulin Huang, Madeleine Linneberg-Agerholm, Alex Faulkner, Athanasios Papathanasiou, Kay Elder, Phil Snell, Leila Christie, Patricia Garcia, Valerie Shaikly, Mohamed Taranissi, Meenakshi Choudhary, Mary Herbert, Courtney W. Hanna, Joshua M. Brickman and Kathy K. Niakan ()
Additional contact information
Claire S. Simon: University of Cambridge
Afshan McCarthy: 1 Midland Road
Laura Woods: University of Cambridge
Desislava Staneva: University of Cambridge
Martin Proks: University of Copenhagen
Nazmus Salehin: University of Copenhagen
Georgia Lea: University of Cambridge
Qiulin Huang: University of Cambridge
Madeleine Linneberg-Agerholm: University of Copenhagen
Alex Faulkner: Newcastle University Centre for Life
Athanasios Papathanasiou: Bourn
Kay Elder: Bourn
Phil Snell: Bourn
Leila Christie: Bourn
Patricia Garcia: Assisted Reproduction and Gynaecology Centre
Valerie Shaikly: Assisted Reproduction and Gynaecology Centre
Mohamed Taranissi: Assisted Reproduction and Gynaecology Centre
Meenakshi Choudhary: Newcastle University Centre for Life
Mary Herbert: Newcastle University Centre for Life
Courtney W. Hanna: University of Cambridge
Joshua M. Brickman: University of Copenhagen
Kathy K. Niakan: University of Cambridge

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Studies in the mouse demonstrate the importance of fibroblast growth factor (FGF) and extra-cellular receptor tyrosine kinase (ERK) in specification of embryo-fated epiblast and yolk-sac-fated hypoblast cells from uncommitted inner cell mass (ICM) cells prior to implantation. Molecular mechanisms regulating specification of early lineages in human development are comparatively unclear. Here we show that exogenous FGF stimulation leads to expanded hypoblast molecular marker expression, at the expense of the epiblast. Conversely, we show that specifically inhibiting ERK activity leads to expansion of epiblast cells functionally capable of giving rise to naïve human pluripotent stem cells. Single-cell transcriptomic analysis indicates that these epiblast cells downregulate FGF signalling and maintain molecular markers of the epiblast. Our functional study demonstrates the molecular mechanisms governing ICM specification in human development, whereby segregation of the epiblast and hypoblast lineages occurs during maturation of the mammalian embryo in an ERK signal-dependent manner.

Date: 2025
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DOI: 10.1038/s41467-025-61830-x

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