A single-cell molecular map of mouse gastrulation and early organogenesis
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Across the animal kingdom, gastrulation represents a key developmental event during which embryonic pluripotent cells diversify into lineage-specific precursors that will generate the adult organism. Here we report the transcriptional profiles of 116,312 single cells from mouse embryos collected at nine sequential time points ranging from 6.5 to 8.5 days post-fertilization. We construct a molecular map of cellular differentiation from pluripotency towards all major embryonic lineages, and explore the complex events involved in the convergence of visceral and primitive streak-derived endoderm. Furthermore, we use single-cell profiling to show that Tal1-/- chimeric embryos display defects in early mesoderm diversification, and we thus demonstrate how combining temporal and transcriptional information can illuminate gene function. Together, this comprehensive delineation of mammalian cell differentiation trajectories in vivo represents a baseline for understanding the effects of gene mutations during development, as well as a roadmap for the optimization of in vitro differentiation protocols for regenerative medicine.
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The study found overwhelming agreement between its cluster annotations and those of Pijuan-Sala et al. (2019), apart from cells annotated as surface ectoderm.
“We found overwhelming agreement between our respective cluster annotations, apart from cells annotated as surface ectoderm from Pijuan-Sala et al. (2019)”
From Single-Cell Transcriptomics Reveals Early Emergence of Liver Parenchymal and Non-parenchymal Cell Lineages (2020) · cites this paper as Pijuan-Sala et al., 2019
The Methods section, “Clustering and cell annotation” (page unavailable), confirms that Pijuan-Sala et al. produced cluster-level cell-type annotations, so the citation identifies an appropriate comparison atlas. Our copy does not identify a surface-ectoderm annotation. The reported agreement and exception are the citing authors’ own findings, not results claimed by Pijuan-Sala et al. (LLM, conf=0.78)
Experimental — accuracy not yet measuredOverlapping TF gradients accompany cellular differentiation in systems including exit from pluripotency, organogenesis, and tissue regeneration by adult stem cells.
“Similar overlapping TF gradients accompany cellular differentiation in systems ranging from the exit from pluripotency5 over organogenesis6 to tissue regeneration by other adult stem cells.7,8”
From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [6]
Citation 6 attaches to organogenesis, not to the separately cited claims about exit from pluripotency or adult stem cells. In “Mapping endoderm development” (page unavailable), the paper reports transcription factors with sequential activation profiles during hindgut maturation and specification. This supports changing TF expression during early organogenesis, but the passage does not establish the claimed overlapping TF gradients. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe largest group, epithelial cells, consisted of EPCAM+TFAP2A+ cells expressing markers of nascent surface ectoderm (HAND1+), epidermal progenitors (WNT6+TP63+), and anterior (SIX1+PAX6+DLX5+) and posterior (SIX1+PAX8+GBX2+) cranial placodes.
“The largest group, epithelial cells, consisted of EPCAM+TFAP2A+ cells expressing markers of nascent surface ectoderm (HAND1+), epidermal progenitors (WNT6+TP63+), and anterior (SIX1+PAX6+DLX5+) and posterior (SIX1+PAX8+GBX2+) cranial placodes (Fig. 2a–d, Extended Data Fig. 5)11,20.”
From Hair-bearing human skin generated entirely from pluripotent stem cells (2020) · cites this paper as [20]
The single-cell map section reports the emergence of ectodermal lineages, but does not describe the claimed epithelial group or its marker-defined subtypes. Searches for the specified genes and cranial placodes found no supporting passage; the Epcam mention in Mapping endoderm development concerns gut epithelial remodelling instead. (LLM, conf=0.76)
Experimental — accuracy not yet measuredCellOracle reproduced the inhibited differentiation of haematoendothelial progenitors in the Tal1 KO.
“CellOracle reproduced the inhibited differentiation of haematoendothelial progenitors in the Tal1 KO30 (Extended Data Fig. 9e–h).”
From Dissecting cell identity via network inference and in silico gene perturbation (2023) · cites this paper as [30]
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A single-embryo, single-cell time-resolved model for mouse gastrulation
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Unraveling Hematopoiesis through the Lens of Genomics
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Self-citationCell diversity and plasticity during atrioventricular heart valve EMTs
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“Single-cell RNA sequencing (scRNA-seq) has been successfully applied to chart transcriptional diversity within the early embryo 34,35 , heart 36 , liver 37,38 , and others.”
Method
- Authors
- Pijuan-Sala, B., Griffiths, J. A., Guibentif, C., Hiscock, T. W., Jawaid, W., Calero-Nieto, F. J., Mulas, C., Ibarra-Soria, X., Tyser, R. C. V., Ho, D. L. L., Reik, W., Srinivas, S., Simons, B. D., Nichols, J., Marioni, J. C., & Göttgens, B.
- Affiliations
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- University of Oxford (GB)
- Babraham Institute (GB)
- European Bioinformatics Institute (GB)
- Corresponding author
- Marioni, John C.
- Göttgens, Berthold
- ORCID
- Venue
- Nature
- Published
- 2019-02
- Volume
- 566
- Issue
- 7745
- Pages
- 490-495
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6522369
- OpenAlex
- W2912272542
- Cited by
- 1,033
- References
- 60
- Citations by year
- 2026: 122 · 2025: 173 · 2024: 170 · 2023: 129 · 2022: 134 · 2021: 151 · 2020: 94 · 2019: 57 · 2018: 2 · 2013: 1
- FWCI
- 36.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (206328/Z/17/Z, 108438/E/15/Z, 109081/Z/15/Z, 105031, 206328, 097922/B/11/Z, 098357/Z/12/Z, 079895/Z/06/Z, 105031/D/14/Z, 105031/Z/14/Z, 097922, 079895, 103788/Z/14/Z, 100140/Z/12/Z, 203151/Z/16/Z, 109081, 079895/Z/06/B, 097922/Z/11/B, 109081/Z/15/A, 203151)
- Cancer Research UK (A21762, 21762, C14303 / A17197)
- British Heart Foundation (FS/18/24/33424)
- Medical Research Council (MR/M008975/1, MC_PC_12009)
- Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0422, BBS/E/B/000C0421, BB/J00989X/1)
- National Institute of Diabetes and Digestive and Kidney Diseases (R24DK106766)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- gastrulation, early organogenesis, mouse embryo, single-cell transcriptomics, cell differentiation trajectories, embryonic lineage, endoderm, mesoderm, visceral endoderm, primitive endoderm, TAL1, chimeric embryos, pluripotency, developmental gene function, in vitro differentiation
- MeSH terms
- T-Cell Acute Lymphocytic Leukemia Protein 1, Animals, Cell Differentiation, Chimera, Embryo, Mammalian, Endoderm, Endothelium, Female, Hematopoiesis, Male, Mesoderm, Mutation, Gene Expression Regulation, Developmental, Cell Lineage, Gene Expression Profiling, Myeloid Cells, Organogenesis, Pluripotent Stem Cells, Mice, Primitive Streak, Gastrulation, Single-Cell Analysis
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