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Cited by 383Single-cell and spatial transcriptomicsDevelopmental Biology and Gene RegulationPluripotent Stem Cells Research

The emergent landscape of the mouse gut endoderm at single-cell resolution

Open access
Nowotschin, Sonja, Setty, Manu, Kuo, Ying-Yi, Liu, Vincent, Garg, Vidur, Sharma, Roshan, Simon, Claire S., Saiz, Nestor +6 more·2019·Nature
DOI 10.1038/s41586-019-1127-1PMC PMC6724221
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Abstract

Here we delineate the ontogeny of the mammalian endoderm by generating 112,217 single-cell transcriptomes, which represent all endoderm populations within the mouse embryo until midgestation. We use graph-based approaches to model differentiating cells, which provides a spatio-temporal characterization of developmental trajectories and defines the transcriptional architecture that accompanies the emergence of the first (primitive or extra-embryonic) endodermal population and its sister pluripotent (embryonic) epiblast lineage. We uncover a relationship between descendants of these two lineages, in which epiblast cells differentiate into endoderm at two distinct time points-before and during gastrulation. Trajectories of endoderm cells were mapped as they acquired embryonic versus extra-embryonic fates and as they spatially converged within the nascent gut endoderm, which revealed these cells to be globally similar but retain aspects of their lineage history. We observed the regionalized identity of cells along the anterior-posterior axis of the emergent gut tube, which reflects their embryonic or extra-embryonic origin, and the coordinated patterning of these cells into organ-specific territories.

AI snapshot

Written from the paper’s full text.

TL;DR

This study generated 112,217 single-cell transcriptomes spanning mouse endoderm from E3.5 to E8.75 and used graph-based trajectory inference to map endoderm ontogeny. It shows that epiblast cells contribute to endoderm before and during gastrulation, that embryonic and extra-embryonic endoderm converge transcriptionally in the gut tube while retaining lineage memory, and that anterior-posterior organ territories are transcriptionally primed before overt organ formation.

Key findings

  • Profiled 112,217 cells across 13 tissue types from E3.5 to E8.75, covering primitive/extra-embryonic endoderm, definitive/embryonic endoderm, and emergent gut endoderm.
  • Identified an epiblast-to-endoderm contribution: a subset of EPI cells acquired endoderm identity before gastrulation, validated by Sox2-Cre lineage tracing (GFP-positive cells in emVE: 1–5 cells, 10/20 embryos) and tetraploid ESC chimeras (1–5 cells, 9/19 embryos); Ttr-Cre tracing showed no EPI contribution from VE (0/27 embryos).
  • VE and DE descendants intermixed along the E8.75 gut tube AP axis, with DE enriched anteriorly and VE posteriorly; a classifier trained on E7.5 VE/DE cells achieved auROC 0.96 and predicted E8.75 origin with auROC 0.92, indicating retained lineage history.
  • E8.75 gut tube cells ordered along AP pseudo-space matched the stereotypical order of organ identities; TF expression predicted AP pseudo-space with correlation 0.97, and a core set of 20 TFs was identified.

Methods

  • Mouse embryos were collected from E3.5 to E8.75; pre-/early post-implantation stages used whole embryos, while E6.5–E8.75 used endodermal tissue enrichment, including Afp-GFP FACS to separate GFP-positive extra-embryonic and GFP-negative embryonic populations.
  • Single-cell 3′ RNA-seq libraries were generated on the 10x Genomics Chromium platform, with 13 tissue types collected in duplicate or triplicate; bulk RNA-seq, in situ hybridization, immunofluorescence, and lineage tracing were used for validation.
  • Computational analysis combined Harmony to bridge time-points with Palantir for pseudo-time, branch probabilities, and differentiation potential; Phenograph and tSNE were used for clustering/visualization, plus manifold classifiers and sparse regression models for AP pseudo-space and VE/DE classification.

Limitations

  • The paper states that investigators were not blinded to allocation during experiments and outcome assessment.
  • No formal limitations section is present; the text makes evident that findings are restricted to the mouse embryo and rely heavily on computational trajectory inference, with many predictions validated by imaging/ISH rather than functional perturbation.
  • The study notes that Afp-GFP/Ttr-Cre-based discrimination of VE versus DE origin was limited to stages up to E8.75, the latest stage analyzed.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41586-019-1127-1

Cites

57 of 57 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

43 of 60 cited sources checked · 27 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    ICM lineage divergence into EPI and PrE occurs at E3.5.

    “The changes in DP and BP suggest ICM lineage divergence into EPI and PrE occurs at E3.5 consistent with previous analyses using limited markers20,21”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [20] Plusa, B., Piliszek, A., Frankenberg, S., Artus, J. & Hadjantonakis, A. K. Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst. Development 135, 3081–3091 (2008). source
    • cites [21] Chazaud, C., Yamanaka, Y., Pawson, T. & Rossant, J. Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Dev. Cell 10, 615–624 (2006). source
    • The authors state this as an assumption: Regions along pseudo-time where differentiation potential drops represent points where lineage specification and commitment occur.
  • Premisecitation

    The gut endoderm is comprised of cells of both PrE and DE.

    “Our previous studies revealed the gut endoderm to be comprised of cells of both PrE and DE (Extended Data Fig. 1a)5–7.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [5] Viotti, M., Nowotschin, S. & Hadjantonakis, A. K. SOX17 links gut endoderm morphogenesis and germ layer segregation. Nat. Cell Biol. 16, 1146–1156 (2014). source
    • cites [6] Viotti, M., Nowotschin, S. & Hadjantonakis, A. K. Afp:mCherry, a red fluorescent transgenic reporter of the mouse visceral endoderm. Genesis 49, 124–133 (2011). source
    • cites [7] Kwon, G. S., Viotti, M. & Hadjantonakis, A. K. The endoderm of the mouse embryo arises by dynamic widespread intercalation of embryonic and extraembryonic lineages. Dev. Cell 15, 509–520 (2008). source
  • Interpretationcitation

    Two PrE clusters at E3.5 represent nascent and more advanced populations during lineage maturation.

    “We also identified two PrE clusters at E3.5, which we propose represent nascent (light blue) and more advanced (dark blue) populations during lineage maturation22”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] Artus, J., Piliszek, A. & Hadjantonakis, A. K. The primitive endoderm lineage of the mouse blastocyst: sequential transcription factor activation and regulation of differentiation by Sox17. Dev. Biol. 350, 393–404 (2011). source
    • The authors state this as an assumption: Regions along pseudo-time where differentiation potential drops represent points where lineage specification and commitment occur.
  • Findingcitation

    TE cells were substantially further away (average diffusion distance 13.9) from ICM than EPI (0.41) or PrE (2.0).

    “Based on the average diffusion distance10,11 from the bipotent inner cell mass (ICM), TE cells were substantially further away (13.9) from ICM than either EPI (0.41) or PrE (2.0) (Extended Data Fig. 4b, Methods)”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [10] Setty, M. et al. Palantir characterizes cell fate continuities in human hematopoiesis. Preprint at https://www.biorxiv.org/content/early/2018/08/05/385328 (2018). source
    • cites [11] Setty, M. et al. Characterization of cell fate probabilities in single-cell data with Palantir. Nat. Biotechnol. 37, 451–460 (2019). source
  • Findingown data

    These analyses provide precise ordering of markers during ICM lineage specification.

    “These analyses provide precise ordering of markers during ICM lineage specification (Extended Data Fig. 5c)3,22,28.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [3] Chazaud, C. & Yamanaka, Y. Lineage specification in the mouse preimplantation embryo. Development 143, 1063–1074 (2016). source
    • cites [22] Artus, J., Piliszek, A. & Hadjantonakis, A. K. The primitive endoderm lineage of the mouse blastocyst: sequential transcription factor activation and regulation of differentiation by Sox17. Dev. Biol. 350, 393–404 (2011). source
    • cites [28] Ohnishi, Y. et al. Cell-to-cell expression variability followed by signal reinforcement progressively segregates early mouse lineages. Nat. Cell Biol. 16, 27–37 (2014). source

      The Results section (‘Progressive establishment of correlation’; page unavailable) reports an approximate activation hierarchy for seven PrE markers during the E3.5–E4.5 transition. It says evidence for a hierarchy was much weaker earlier, so it does not establish a precise ordering of markers throughout ICM lineage specification. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 47
  • The quote only partly states this claim. 1

  • Classified as probably not a substantial claim.

    Premisecitation

    Definitive (embryonic) endoderm (DE) is specified from pluripotent epiblast (EPI) at gastrulation around E7.0.

    “Later, around E7.0, definitive (embryonic) endoderm (DE) is specified from pluripotent epiblast (EPI) at gastrulation4.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] Nowotschin, S. & Hadjantonakis, A. K. Cellular dynamics in the early mouse embryo: from axis formation to gastrulation. Curr. Opin. Genet. Dev. 20, 420–427 (2010). source

      The ‘Emergence of the primitive streak’ section says that during gastrulation the epiblast generates definitive endoderm, and ‘Intercalation and endoderm morphogenesis’ says DE cells may be specified within the streak. The paper places streak formation at E6.5 and its elongation through E7.5, but does not specifically place DE specification around E7.0. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The gut endoderm is the precursor of the respiratory and digestive tracts and their associated organs.

    “The gut endoderm is the precursor of the respiratory and digestive tracts, and their associated organs1,2 (Fig. 1).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [1] Zorn, A. M. & Wells, J. M. Vertebrate endoderm development and organ formation. Annu. Rev. Cell Dev. Biol. 25, 221–251 (2009). source
    • cites [2] Tremblay, K. D. Formation of the murine endoderm: lessons from the mouse, frog, fish, and chick. Prog. Mol. Biol. Transl. Sci. 96, 1–34 (2010). source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    ICM cell fate specification is driven in part by lineage-specific TFs Gata6 and Nanog, co-expressed in uncommitted ICM and exclusively expressed in and required for PrE and EPI respectively.

    “ICM cell fate specification is driven in part by the lineage-specific transcription factors (TFs) Gata6 and Nanog, which are co-expressed in uncommitted ICM, and exclusively expressed in, and required for, PrE and EPI respectively23,24.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [23] Silva, J. et al. Nanog is the gateway to the pluripotent ground state. Cell 138, 722–737 (2009). source

      The Results section on Nanog localization (page not provided) identifies Gata6 as a hypoblast specification factor and reports that Gata6 and Nanog occupy mutually exclusive cells by E4.5. The Discussion (page not provided) says Nanog is exclusively expressed in nascent epiblast and is essential for its transition to pluripotency. Our copy does not establish that Gata6 and Nanog are co-expressed in uncommitted ICM cells or that Gata6 is required for primitive endoderm formation. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [24] Schrode, N., Saiz, N., Di Talia, S. & Hadjantonakis, A. K. GATA6 levels modulate primitive endoderm cell fate choice and timing in the mouse blastocyst. Dev. Cell 29, 454–467 (2014). source

      The Introduction and Results describe GATA6 and NANOG as lineage-specific transcription factors that are initially co-expressed in ICM cells and later become mutually exclusive in PrE and EPI precursors. The Results establish that GATA6 is required for PrE specification. Our copy identifies NANOG with EPI but does not establish that NANOG is required for EPI specification. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The early post-implantation (E5.5) mouse embryo is radially symmetrical, and the VE appears morphologically uniform around its proximal-distal axis.

    “The early post-implantation (E5.5, Fig. 1) mouse embryo is radially symmetrical, and the VE appears morphologically uniform around its proximal-distal axis4,33.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [4] Nowotschin, S. & Hadjantonakis, A. K. Cellular dynamics in the early mouse embryo: from axis formation to gastrulation. Curr. Opin. Genet. Dev. 20, 420–427 (2010). source

      The section “PD polarity at early postimplantation results in DVE cell specification” describes the E5.5 egg cylinder as radially symmetric. It does not establish that the VE appears morphologically uniform around the proximal-distal axis; instead, it describes distinct proximal and distal VE morphologies and morphologically distinct DVE cells around E5.5. The source therefore supports the embryo-symmetry part but not the unqualified VE-uniformity part. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [33] Arnold, S. J. & Robertson, E. J. Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nat. Rev. Mol. Cell Biol. 10, 91–103 (2009). source

  • May combine two claims.

    Premisecitation

    FGF4 signaling is active across the ICM population and is critical for PrE specification.

    “While active across the ICM population25–27, FGF4 signaling is critical for PrE specification28,29.”
    Quote in the paperNot a substantial claim4 of 5 sources checked
    • cites [25] Morgani, S. M. et al. A Sprouty4 reporter to monitor FGF/ERK signaling activity in ESCs and mice. Dev. Biol. 441, 104–126 (2018). source
    • cites [26] Molotkov, A., Mazot, P., Brewer, J. R., Cinalli, R. M. & Soriano, P. Distinct requirements for FGFR1 and FGFR2 in primitive endoderm development and exit from pluripotency. Dev. Cell 41, 511–526 (2017). source

      The citation is attached to the claim that FGF4 signaling is critical for PrE specification, not to the preceding claim about activity across the ICM. The Discussion says FGF4 promotes conversion of ICM cells toward a PrE fate. However, the Results section “Fgfr1 and Fgfr2 are Required for Maintenance but not Initiation of the PrE” says PrE development begins without FGF signaling but is not maintained, so the claim overstates its role in initial specification. Page numbers were not available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [27] Kang, M., Garg, V. & Hadjantonakis, A. K. Lineage establishment and progression within the inner cell mass of the mouse blastocyst requires FGFR1 and FGFR2. Dev. Cell 41, 496–510 (2017). source
    • cites [28] Ohnishi, Y. et al. Cell-to-cell expression variability followed by signal reinforcement progressively segregates early mouse lineages. Nat. Cell Biol. 16, 27–37 (2014). source
    • cites [29] Kang, M., Piliszek, A., Artus, J. & Hadjantonakis, A. K. FGF4 is required for lineage restriction and salt-and-pepper distribution of primitive endoderm factors but not their initial expression in the mouse. Development 140, 267–279 (2013). source

  • May combine two claims.

    Interpretationown data

    emVE represents a specialized variant of exVE, perhaps modulating a transcriptional program in response to stimuli such as BMP or Nodal.

    “Differential expression between bulk RNA sequenced E7.5 exVE and emVE populations suggested that emVE represents a specialized variant of exVE (Extended Data Fig. 7d), perhaps modulating a transcriptional program in response to stimuli, such as BMP or Nodal38–40.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [38] Paca, A. et al. BMP signaling induces visceral endoderm differentiation of XEN cells and parietal endoderm. Dev. Biol. 361, 90–102 (2012). source
    • cites [39] Kruithof-de Julio, M. et al. Regulation of extra-embryonic endoderm stem cell differentiation by Nodal and Cripto signaling. Development 138, 3885–3895 (2011). source
    • cites [40] Artus, J. et al. BMP4 signaling directs primitive endoderm-derived XEN cells to an extraembryonic visceral endoderm identity. Dev. Biol. 361, 245–262 (2012). source

      In Results and Discussion (page unavailable), the paper reports that BMP4 changes gene expression in XEN cells toward an exVE-like identity, supporting BMP as a stimulus that can modulate a visceral-endoderm program. It does not show that emVE is a specialized variant of exVE or that emVE modulates its program in response to BMP. The Introduction mentions Nodal-induced XEN-cell differentiation, but does not establish a Nodal response in emVE. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Proximal-distal spatial patterning across the VE has been described preceding and coincident to onset of gastrulation at E6.5, with clear distinction between morphology and function of proximally located exVE and distal emVE.

    “Proximal-distal spatial patterning across the VE has been described preceding, and coincident to the onset of gastrulation at E6.5, with a clear distinction between the morphology and function of the proximally located exVE (cuboidal epithelium, overlying the ExE, giving rise to yolk sac endoderm, YsE) and distal emVE (squamous epithelium, overlying the epiblast, contributing to the gut tube7).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Kwon, G. S., Viotti, M. & Hadjantonakis, A. K. The endoderm of the mouse embryo arises by dynamic widespread intercalation of embryonic and extraembryonic lineages. Dev. Cell 15, 509–520 (2008). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Cell fate is determined through a combination of cell intrinsic propensities to specific fates and extrinsic cues from the environment.

    “Cell fate is determined through a combination of cell intrinsic propensities to specific fates and extrinsic cues (e.g. signaling) from the environment, detailed knowledge of which should yield improved protocols for differentiation into distinct endodermal derivatives49.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [49] McCauley, H. A. & Wells, J. M. Pluripotent stem cell-derived organoids: using principles of developmental biology to grow human tissues in a dish. Development 144, 958–962 (2017). source

      The Introduction explains that external signals, including Wnt and FGF, direct PSC-derived endoderm toward distinct fates, supporting the role of extrinsic cues and their use in differentiation protocols. It does not establish the claimed contribution of cell-intrinsic propensities to fate determination. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationown data

    TF expression was exceptionally accurate in predicting AP pseudo-space order (correlation 0.97), indicating that transcriptional regulation, presumably in response to signals from neighboring mesenchyme, plays a key role in gut tube patterning.

    “TF expression was exceptionally accurate in predicting AP pseudo-space order (Extended Data Fig. 9c, Correlation: 0.97), indicating that transcriptional regulation, presumably in response to signals from neighboring mesenchyme1, plays a key role in gut tube patterning.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Zorn, A. M. & Wells, J. M. Vertebrate endoderm development and organ formation. Annu. Rev. Cell Dev. Biol. 25, 221–251 (2009). source

  • Classified as probably not a substantial claim.

    Premisecitation

    The high resolution achieved by Palantir allows detailed mapping of gene expression trends and dynamics that are correlated with changes in lineage potential.

    “The high resolution achieved by Palantir allows detailed mapping of gene expression trends and dynamics that are correlated with changes in lineage potential10,11.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [10] Setty, M. et al. Palantir characterizes cell fate continuities in human hematopoiesis. Preprint at https://www.biorxiv.org/content/early/2018/08/05/385328 (2018). source
    • cites [11] Setty, M. et al. Characterization of cell fate probabilities in single-cell data with Palantir. Nat. Biotechnol. 37, 451–460 (2019). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Palantir models cell fate choices as continuous probabilistic processes rather than treating lineage decisions as bifurcations.

    “A key distinguishing feature of Palantir is that rather than treating lineage decisions as bifurcations, cell fate choices are modeled as continuous probabilistic processes.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [10] Setty, M. et al. Palantir characterizes cell fate continuities in human hematopoiesis. Preprint at https://www.biorxiv.org/content/early/2018/08/05/385328 (2018). source
    • cites [11] Setty, M. et al. Characterization of cell fate probabilities in single-cell data with Palantir. Nat. Biotechnol. 37, 451–460 (2019). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Palantir results are robust to the parameters used.

    “Palantir results however have been shown to be robust to these parameters10,11,”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [10] Setty, M. et al. Palantir characterizes cell fate continuities in human hematopoiesis. Preprint at https://www.biorxiv.org/content/early/2018/08/05/385328 (2018). source
    • cites [11] Setty, M. et al. Characterization of cell fate probabilities in single-cell data with Palantir. Nat. Biotechnol. 37, 451–460 (2019). source

  • May combine two claims.

    Findingown data

    Using mnnCorrect for global batch effect correction leads to over-correction and loss of signal between time-points.

    “Right: Plot generated using mnnCorrect27 for global batch effect correction leading to “over-correction” and loss in signal between time-points.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [27] Kang, M., Garg, V. & Hadjantonakis, A. K. Lineage establishment and progression within the inner cell mass of the mouse blastocyst requires FGFR1 and FGFR2. Dev. Cell 41, 496–510 (2017). source

      The STAR METHODS sections describe fluorescence-decay correction and normalization of single-cell gene-expression data, but do not discuss mnnCorrect or global batch-effect correction. The Results report that E3.5 and E4.5 cells generally clustered apart, but do not assess over-correction or loss of signal between time-points. Searches for mnnCorrect and batch correction found no passage addressing the claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Endoderm cells that acquired embryonic versus extra-embryonic fates were globally similar but retained aspects of their lineage history.

    “Trajectories of endoderm cells were mapped as they acquired embryonic versus extra-embryonic fates, and as they spatially converged within the nascent gut endoderm; revealing them to be globally similar but retaining aspects of their lineage history.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Gata6/Fgf4 also tracked with EPI specification but trailed Gata6/Nanog.

    “Gata6/Fgf4 also tracked with EPI specification, but trailed Gata6/Nanog.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At E5.5, GFP-positive Gata6-positive cells were observed in distal locations, whereas by E6.0 they predominantly resided more anteriorly.

    “At E5.5, GFP-positive Gata6-positive cells were observed in distal locations, whereas by E6.0, they predominantly resided more anteriorly (Extended Data Fig. 6f).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Additional genes correlated along pseudo-time with Fgf4 in EPI (e.g., Tcf7l1) and with Gata6 and Gata4 in PrE.

    “Additional genes correlated along pseudo-time with Fgf4 in EPI (e.g. Tcf7l1, Extended Data Fig. 5d, b, e–f, green arrowhead), and Gata6 and Gata4 in PrE (Extended Data Fig. 5b, Supplementary Fig. 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The Gata6/Nanog ratio closely tracked with EPI specification and is a strong descriptor of ICM fate specification.

    “The Gata6/Nanog ratio closely tracked with EPI specification and a strong descriptor of ICM fate specification (Extended Data Fig. 5b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The emergent gut tube shows regionalized identity of cells along the anterior-posterior axis, reflecting their embryonic or extra-embryonic origin, and coordinate patterning into organ-specific territories.

    “We observed the regionalized identity of cells along the anterior-posterior axis of the emergent gut tube, reflecting their embryonic or extra-embryonic origin, and their coordinate patterning into organ-specific territories.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Palantir ordered cells along developmental trajectories with high DP at E3.5, corresponding to EPI-vs.-PrE lineage divergence.

    “Palantir ordered cells along their developmental trajectories with high DP at E3.5, corresponding to EPI-vs.-PrE lineage divergence (Fig. 2b).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Regions along pseudo-time where differentiation potential drops represent points where lineage specification and commitment occur.

  • May combine two claims.

    Findingown data

    In Sox2-Cre;ROSA26mTmG embryos at E5.5-E6.0, the majority of GFP-positive cells were within the EPI, with single cells also observed within the emVE (1-5 cells, 10/20 embryos), but not extra-embryonic VE.

    “Imaging of E5.5-E6.0 Sox2-CreTG/+;ROSA26mTmG/+ embryos revealed the majority of GFP-positive cells within the EPI, with single cells also observed within the emVE (yellow arrowhead, 1–5 cells, 10/20 embryos), but not extra-embryonic (ex)VE.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Findingown data

    Fgfr1 was expressed in uncommitted ICM cells and downregulated upon PrE specification, at the time of transient Fgfr2 activation.

    “Palantir suggested Fgfr1 was expressed in uncommitted ICM cells (Extended Data Fig. 5a, c–d), and downregulated upon PrE specification, at the time of transient Fgfr2 activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In Ttr-Cre;ROSA26mTmG embryos, all GFP-positive cells were restricted to the VE, with no cells detected in the EPI (0/27 embryos).

    “By contrast, all GFP-positive cells were restricted to the VE in Ttr-CreTG/+;ROSA26mTmG embryos, with no cells detected in the EPI (0/27 embryos, Fig. 2e, Extended Data Fig. 6f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two ICM clusters were identified: one uncommitted with equal propensity for PrE or EPI fates, and another uncommitted but started to specify towards PrE or EPI.

    “Two ICM clusters were identified; one representing uncommitted cells having equal propensity for PrE or EPI fates (purple), and another (green), that albeit uncommitted, had started to specify towards PrE or EPI”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Regions along pseudo-time where differentiation potential drops represent points where lineage specification and commitment occur.

  • May combine two claims.

    Findingown data

    The data define previously unappreciated sub-states within well-studied cell populations and uncovered detailed gene expression trends.

    “The data also define previously unappreciated sub-states within well-studied cell populations and uncovered detailed gene expression trends.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of Hox genes expressed within E8.75 gut tube, the majority were posteriorly localized, including several displaying robust, more anterior expression within mesoderm and/or neurectoderm.

    “While not all Hox genes were expressed within the E8.75 gut tube, of those that were, the majority were posteriorly localized (Fig. 5d and Extended Data Fig. 10), including several displaying robust, more anterior expression within mesoderm and/or neurectoderm (Extended Data Fig. 10: Hoxb1, Hoxd4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was a high degree of variability in density of cells along the pseudo-spatial axis, with low density regions between clusters.

    “We observed a high degree of variability in the density of cells along the pseudo-spatial axis (Fig. 5b–c, Extended Data Fig. 9a–b), with low density regions between clusters.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    By E8.75, clusters of cells expressing markers of organ identity could be identified, correlating in AP pseudo-space with stereotypical order of endodermal organs.

    “By the time the gut endoderm has internalized forming the gut tube (E8.75), clusters of cells expressing markers of organ identity could be identified, correlating in AP pseudo-space with the stereotypical order of endodermal organs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BMP, HH, JAK/STAT and HIPPO pathway activation encompassed multiple domains, Nodal signaling was not active at this stage, and both positive and negative read-outs of Retinoic Acid signaling were posteriorly localized.

    “BMP, HH, JAK/STAT and HIPPO pathway activation encompassed multiple domains, Nodal signaling was not active at this stage, while both positive and negative read-outs of Retinoic Acid signaling were posteriorly localized.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    All tested organ marker genes (Nkx2-1, Irx1, Ppy, Pdx1, Fabp1, Hoxb9) were expressed at substantial levels in both VE and DE cells at comparable AP positions, except Nkx2-1, which was exclusive to DE.

    “All genes were expressed at substantial levels in both VE and DE cells, and at comparable AP positions, except for Nkx2–1, which is expressed in the anterior-most cells of the gut tube and therefore exclusive to DE (Fig. 4c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cells specifying towards YsE and gut tube were exVE and emVE, respectively.

    “Based on the expression of marker genes in scRNA-seq data, and correlation to bulk RNA-seq gene expression of sorted E7.5 exVE and emVE tissues, cells specifying towards YsE and gut tube were exVE and emVE, respectively, consistent with reported spatial patterning at these stages (Extended Data Fig. 7c–e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    emVE-specific genes include Lhx1 and Lefty1, and AVE-specific genes include Cer1 and Hhex; exVE-specific genes include Apln and Msx1.

    “emVE-specific genes (Fig. 3c, Cluster 1) included Lhx1 and Lefty1, and AVE-specific genes Cer1 and Hhex30,32,37. ExVE-specific genes (Fig. 3c, Cluster 2) included Apln and Msx1 (Supplementary Table 4).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [30] Thomas, P. Q., Brown, A. & Beddington, R. S. Hex: a homeobox gene revealing peri-implantation asymmetry in the mouse embryo and an early transient marker of endothelial cell precursors. Development 125, 85–94 (1998). source
    • cites [32] Belo, J. A. et al. Cerberus-like is a secreted factor with neutralizing activity expressed in the anterior primitive endoderm of the mouse gastrula. Mech. Dev. 68, 45–57 (1997). source
    • cites [37] Takaoka, K., Yamamoto, M. & Hamada, H. Origin and role of distal visceral endoderm, a group of cells that determines anterior–posterior polarity of the mouse embryo. Nat. Cell Biol. 13, 743–752 (2011). source

  • May combine two claims.

    Findingown data

    The data validate FGF and WNT signaling and reveal NOTCH signaling at the posterior (small/large intestine clusters).

    “Our data validate FGF and WNT, and reveal NOTCH signaling at the posterior (small/large intestine clusters, Fig. 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Two covarying gene sets exhibit contrasting expression patterns in putative E5.5 exVE and emVE cells and distinguish bona fide exVE and emVE cells at E6.5 and E7.5.

    “To explore this further, we identified two covarying gene sets (Supplementary Fig. 5b) exhibiting contrasting expression patterns in putative E5.5 exVE and emVE cells (Fig. 3c), and also distinguished bona fide exVE and emVE cells at E6.5 and E7.5 (Extended Data Fig. 7g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was extensive intermixing of DE and VE descendants along the AP pseudo-space axis, with enrichment of DE descendants in the anterior and VE descendants in the posterior.

    “Consistent with previous findings, there was extensive intermixing of these descendants along the AP pseudo-space axis with enrichment of DE descendants in the anterior, and VE descendants in the posterior (Fig. 4b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    VE cells at E5.5 were distributed across pseudo-time: a subset did not exhibit any change in DP indicating a more uncommitted state, while the majority exhibited altered DP indicating propensity towards YsE-vs.-gut tube.

    “Interestingly, VE cells at E5.5 were distributed across pseudo-time (Extended Data Fig. 7a): a subset did not exhibit any change in DP indicating a more uncommitted state (Extended Data Figs. 7e–f), while the majority exhibited altered DP indicating propensity towards YsE-vs.-gut tube (Extended Data Figs. 7e–f).”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Regions along pseudo-time where differentiation potential drops represent points where lineage specification and commitment occur.

  • The quote only partly states this claim.

    Findingown data

    In E5.5 and E6.0 Sox2-Cre and Ttr-Cre embryos, cells of epiblast (EPI) origin are present within the visceral endoderm (VE) epithelial layer.

    “Yellow arrowheads point cells of epiblast (EPI) origin present within the visceral endoderm (VE) epithelial layer.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Presumptive ParE and VE lineages are marked by black and orange arrowheads, respectively, in gene expression patterns of parietal and visceral endoderm markers.

    “Black and orange arrowheads mark presumptive ParE and VE lineages, respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Tcf7l1 expression in EPI is similar to Fgf4.

    “Gene expression patterns of Tcf7l1 and Nanog depicting similar expression of Tcf7l1 in EPI as Fgf4 (green arrowhead).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At E3.5, the average distance between pairs of ICM and TE cells is 13.9, which is orders of magnitude greater than the distance between pairs of ICM and EPI cells (0.41) or ICM and PrE cells (2.0).

    “The average distance between pairs of ICM and TE cells (13.9) at E3.5 and is orders of magnitude greater than distance between pairs of ICM and EPI (0.41) or PrE (2.0) cells (Fig. 2b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The path from EPI to VE boundary cells includes relatively uniform step sizes and does not include substantially large steps.

    “In contrast, the path from EPI to VE boundary cells includes relatively uniform step sizes and does not include substantially large steps indicating continuity (Extended Data Fig. 6d).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Primitive (extra-embryonic) endoderm (PrE) cells arise at the blastocyst stage, around mouse embryonic day 3.5-4.0, and predominantly contribute to parietal and visceral yolk sac endoderm.

    “Primitive (extra-embryonic) endoderm (PrE) cells arise at the blastocyst stage, around mouse embryonic (E) day 3.5–4.03, and predominantly contribute to parietal and visceral yolk sac endoderm.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Chazaud, C. & Yamanaka, Y. Lineage specification in the mouse preimplantation embryo. Development 143, 1063–1074 (2016). source

  • May combine two claims.

    Interpretationown data

    Trans-migrating cells were Gata6-positive, indicating they had acquired an endoderm identity.

    “Trans-migrating cells were Gata6-positive, indicating they had acquired an endoderm identity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    By E4.5, a second phase of FGF signaling in PrE could be mediated by Fgf5/Fgf8-Fgfr4 in emergent VE and Fgf3-Fgfr3 in ParE.

    “By E4.5, when Fgfr1 and Fgfr2 are no longer expressed, a second phase of FGF signaling in PrE could be mediated by Fgf5/Fgf8-Fgfr4 in emergent VE and Fgf3-Fgfr3 in ParE (Extended Data Fig. 5d, orange and black arrowheads).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Symmetry is broken and the AP axis established through migration of AVE.

    “Symmetry is broken, and the AP axis established through the migration of AVE37.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Takaoka, K., Yamamoto, M. & Hamada, H. Origin and role of distal visceral endoderm, a group of cells that determines anterior–posterior polarity of the mouse embryo. Nat. Cell Biol. 13, 743–752 (2011). source

  • May combine two claims.

    Study design and conductown data

    Isolation and dissociation did not alter cell proportions or transcriptional profiles.

    “Comparison to bulk RNA-seq data demonstrated that isolation and dissociation did not alter cell proportions or transcriptional profiles (Extended Data Figs. 1c, 2b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Cluster-specific expression was validated using ISH, confirming accuracy of inferred AP pseudo-space and emergence of endodermal organ identities at E8.75.

    “Cluster-specific expression was validated using ISH, confirming the accuracy of inferred AP pseudo-space, and the emergence of endodermal organ identities at E8.75 (Extended Data Fig. 9a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The inferred pseudo-space was robust to different parameters and reproducible across replicates.

    “The inferred pseudo-space was robust to different parameters and reproducible across replicates (Extended Data Fig. 8e–g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Cells develop a marked propensity towards specific cell fates earlier than previously appreciated, yet retain a remarkable degree of plasticity.

    “While cells develop a marked propensity towards specific cell fates earlier than previously appreciated, they nevertheless retain a remarkable degree of plasticity.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Regions along pseudo-time where differentiation potential drops represent points where lineage specification and commitment occur.

  • May combine two claims.

    Study design and conductown data

    Gene expression trends from scRNA-seq data were consistent with bulk RNA-seq data of micro-dissected gut tube quadrants, with Nkx2-1 anterior and Hoxb9 posterior exhibiting consistent expression patterns.

    “To corroborate AP ordering reflecting spatial distribution along the gut tube, we confirmed consistency between gene expression trends from scRNA-seq data with bulk RNA-seq data of micro-dissected gut tube quadrants, such that Nkx2–1 an anterior gene, and Hoxb9, a posterior gene, exhibited consistent expression patterns (Extended Data Fig. 8c).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All bulk RNA-seq samples were generated in duplicate.

    “All samples were generated in duplicate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    At the transcriptional level, spatial patterning exists at E5.5, preceding morphological changes within the VE.

    “Taken together, these data reveal that at the transcriptional level, spatial patterning exists at E5.5, preceding morphological changes within the VE.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: Regions along pseudo-time where differentiation potential drops represent points where lineage specification and commitment occur.

  • May combine two claims.

    Interpretationown data

    Gut tube AP patterning and stereotypical emergence of organ identities precede or are independent of a Hox code.

    “These data suggest that gut tube AP patterning and the stereotypical emergence of organ identities, precede or are independent of a Hox code.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Wherever possible, purity checks indicated >99.9% sample purity.

    “Wherever possible, purity checks were performed indicating >99.9% sample purity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    VE and DE descendants retain a signature of their lineage history but largely acquire transcriptomic equivalence.

    “While we show that VE and DE descendants retain a signature of their lineage history, the data suggest they largely acquire transcriptomic equivalence.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The entropy of Palantir branch probabilities represents a quantitative measure of the differentiation potential or plasticity of a cell, with multipotent cells having the highest differentiation potential and mature terminal states the lowest.

    “The entropy of these branch probabilities has been shown to represent a quantitative measure of the differentiation potential or plasticity of the cell, where multipotent cells have the highest differentiation potential and mature terminal states have the lowest potential.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The investigators were not blinded to allocation during experiments and outcome assessment.

    “The investigators were not blinded to allocation during experiments and outcome assessment.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Hox gene expression in the developing central nervous system is considered a canonical descriptor of AP axis position.

    “Hox gene expression in the developing central nervous system is considered a canonical descriptor of AP axis position46.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Deschamps, J. & van Nes, J. Developmental regulation of the Hox genes during axial morphogenesis in the mouse. Development 132, 2931–2942 (2005). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The annotations and STAR parameters used for single-cell RNA-seq data alignment were also used for bulk RNA-seq data to maintain consistency.

    “The annotations and STAR parameters used for single cell RNA-seq data alignment were also used for bulk RNA-seq data to maintain consistency.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All subcloned in situ hybridization probes were validated by sequencing.

    “All subcloned ISH probes were validated by sequencing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Single-cell 3' RNA-seq libraries were generated in duplicate or triplicate.

    “Cellular suspensions were loaded on a Chromium Controller54 targeting a 2,500–10,000 cell range, depending on tissue type and embryo stage, to generate single cell 3’ RNA-seq libraries, in duplicate or triplicate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The VE is patterned at the onset of post-implantation development, and the emVE, including the AVE subpopulation, are derivative of exVE.

    “These data demonstrate that the VE is patterned at the onset of post-implantation development, and that the emVE, including the AVE subpopulation, are derivative of exVE.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    There was a strong correlation in global gene expression patterns between VE and DE cells in binned locations along AP pseudo-space, suggesting they were similarly patterned and acquiring regionalized organ-specific identities.

    “Furthermore, we noted a strong correlation in global gene expression patterns between VE and DE cells in binned locations along AP pseudo-space (Fig. 4b, purple), suggesting they were similarly patterned and acquiring regionalized organ-specific identities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Differences between consecutive time-points represent underlying developmental changes but are also confounded by technical batch effects, including discontinuity between E3.5 and E4.5 and lack of spatial alignment between E6.5 and E7.5.

    “Differences between consecutive time-points represent underlying developmental changes but are also confounded by technical batch effects, including discontinuity between E3.5 and E.4.5 and lack of spatial alignment between E6.5 and E7.5.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Results in Extended Data Figure 6f were validated in at least three independent experiments.

    “Results validated in at least three independent experiments.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    Key signaling pathways (FGF, WNT, BMP, NOTCH, HH, Nodal/TGF-beta, JAK/STAT, RA, HIPPO) act within the endoderm lineage of the embryo.

    “Force directed layouts of context-independent targets of key signaling pathways acting within the endoderm lineage of the embryo.”
    Quote in the paperNot a substantial claim
66 of 66

  • The paper relies on this without support.

    The dynamics of key transcription factors and signaling pathway components within the ICM remain unclear.

    “The dynamics of key TFs and signaling pathway components within the ICM remain unclear.”

  • The authors state this as an assumption.

    Regions along pseudo-time where differentiation potential drops represent points where lineage specification and commitment occur.

    “Regions along pseudo-time where DP drops represent points where lineage specification and commitment occur.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • PCA dimensionality reduction and mutual-nearest neighbours or Harmony batch correction was performed to correct for non-biological confounders between replicates and timepoints.

    “PCA dimensionality reduction and mutual-nearest neighbours84 or Harmony34 batch correction was performed to correct for non-biological confounders between replicates and timepoints.”

    From Cell diversity and plasticity during atrioventricular heart valve EMTs (2023) · cites this paper as [34]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Classifier accuracy cites the wrong panel

    Minor

    The Results cite Extended Data Fig. 8h for the E7.5 classifier's accuracy, whereas the caption describes the classifier's receiver operating curve in panel e and a different analysis in panel h.

  • Orange and black arrowheads identify opposite lineages

    Minor

    The Results assign the orange arrowhead to VE and the black arrowhead to ParE in Extended Data Fig. 5d, but that figure's caption assigns orange to ParE and black to VE.

  • VE-proportion comparison cites a replicate-ordering panel

    Minor

    The Results cite Extended Data Fig. 8m for the comparison between embryo VE proportions and AP pseudo-space. The caption describes that comparison in panel j, while panel m compares pseudo-space orderings across replicates.

  • AP-priming result cites a robustness panel

    Minor

    The Results cite Extended Data Fig. 8k for E7.5 anterior-posterior priming. The caption assigns that analysis to panel h; panel k instead concerns robustness of pseudo-space ordering.

4 of 4

Cites

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Related

Authors
Nowotschin, S., Setty, M., Kuo, Y.-Y., Liu, V., Garg, V., Sharma, R., Simon, C. S., Saiz, N., Gardner, R., Boutet, S. C., Church, D. M., Hoodless, P. A., Hadjantonakis, A.-K., & Pe’er, D.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • 10X Genomics (United States) (US)
  • BC Cancer Agency (CA)
Corresponding author
  • Hadjantonakis, Anna-Katerina
  • Pe’er, Dana
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2019-04-08
Volume
569
Issue
7756
Pages
361-367
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-019-1127-1
PMC
PMC6724221
OpenAlex
W2929173597
Cited by
383
References
57
Citations by year
2026: 43 · 2025: 46 · 2024: 64 · 2023: 63 · 2022: 52 · 2021: 52 · 2020: 44 · 2019: 18 · 2018: 1
FWCI
11.88
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health (4r01ca164729-05)
  • National Cancer Institute (R01-CA164729, P30CA008748)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK084391)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (DP1HD084071, R01HD094868)
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
gut endoderm, mouse embryo, single-cell transcriptomics, extraembryonic endoderm, primitive endoderm, gastrulation, cell differentiation trajectories, anterior-posterior axis, lineage history
MeSH terms
Animals, Blastocyst, Cell Differentiation, Endoderm, Female, Intestines, Male, Cell Lineage, Body Patterning, Mice, Gastrulation, Single-Cell Analysis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-23.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-23.

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