Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst
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 mech...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61830-x |
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| author | 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 Kathy K. Niakan |
| author_facet | 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 Kathy K. Niakan |
| author_sort | Claire S. Simon |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6ec0c20c7b9441eba0ea0bafee62d5db |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-6ec0c20c7b9441eba0ea0bafee62d5db2025-08-20T03:46:15ZengNature PortfolioNature Communications2041-17232025-07-0116111310.1038/s41467-025-61830-xSuppression of ERK signalling promotes pluripotent epiblast in the human blastocystClaire S. Simon0Afshan McCarthy1Laura Woods2Desislava Staneva3Martin Proks4Nazmus Salehin5Georgia Lea6Qiulin Huang7Madeleine Linneberg-Agerholm8Alex Faulkner9Athanasios Papathanasiou10Kay Elder11Phil Snell12Leila Christie13Patricia Garcia14Valerie Shaikly15Mohamed Taranissi16Meenakshi Choudhary17Mary Herbert18Courtney W. Hanna19Joshua M. Brickman20Kathy K. Niakan21Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of CambridgeHuman Embryo and Stem Cell Laboratory, The Francis Crick Institute, 1 Midland RoadLoke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of CambridgeLoke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of CambridgeNovo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Science, University of CopenhagenNovo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Science, University of CopenhagenLoke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of CambridgeLoke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of CambridgeNovo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Science, University of CopenhagenNewcastle Fertility Centre, Newcastle upon Tyne Hospitals NHS Trust, Biosciences Institute, Newcastle University Centre for LifeBourn Hall Clinic, BournBourn Hall Clinic, BournBourn Hall Clinic, BournBourn Hall Clinic, BournAssisted Reproduction and Gynaecology CentreAssisted Reproduction and Gynaecology CentreAssisted Reproduction and Gynaecology CentreNewcastle Fertility Centre, Newcastle upon Tyne Hospitals NHS Trust, Biosciences Institute, Newcastle University Centre for LifeNewcastle Fertility Centre, Newcastle upon Tyne Hospitals NHS Trust, Biosciences Institute, Newcastle University Centre for LifeLoke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of CambridgeNovo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Department of Biomedical Science, University of CopenhagenLoke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of CambridgeAbstract 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.https://doi.org/10.1038/s41467-025-61830-x |
| spellingShingle | 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 Kathy K. Niakan Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst Nature Communications |
| title | Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst |
| title_full | Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst |
| title_fullStr | Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst |
| title_full_unstemmed | Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst |
| title_short | Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst |
| title_sort | suppression of erk signalling promotes pluripotent epiblast in the human blastocyst |
| url | https://doi.org/10.1038/s41467-025-61830-x |
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