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Lookup NU author(s): Dr Alex Faulkner, Dr Meenakshi Choudhary, Professor Mary Herbert
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2025.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.
Author(s): Simon CS, McCarthy A, Woods L, Staneva D, Proks M, Salehin N, Lea G, Huang Q, Linneberg-Agerholm M, Faulkner A, Papathanasiou A, Elder K, Snell P, Christie L, Garcia P, Shaikly V, Taranissi M, Choudhary M, Herbert M, Hanna CW, Brickman JM, Niakan KK
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2025
Volume: 16
Issue: 1
Print publication date: 01/12/2025
Online publication date: 28/07/2025
Acceptance date: 01/07/2025
Date deposited: 13/08/2025
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-025-61830-x
DOI: 10.1038/s41467-025-61830-x
Data Access Statement: The GEO database under accession codes GSE250613, GSE250614, GSE297052, GSE297478, GSE239843. Processed scRNAseq data is available at Zendo repository 15128175. All PBAT-seq data generated in naïve hESCs are protected due to data privacy laws and are available upon request from the European Genome-phenome Archive EGAD50000001475. Raw confocal microscopy images generated in this study are available at Figshare 28597145. Previously published single-cell RNA-seq data from human embryos were downloaded from GEO accessions GSE36552 and GSE66507 and at EMBL-EBI Array Express accession number E-MTAB-3929. Primed and naive hESC RNAseq datasets were downloaded from the ENA Browser https://www.ebi.ac.uk/ ena/browser/home accessions PRJEB7132 [https://www.ebi.ac.uk/ena/ browser/view/PRJEB7132], PRJNA522065, PRJNA575370, PRJEB12748, and PRJEB47485. The remaining data and code access statement in available in the paper.
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