CoChat
Sign Up
Cited by 174Pluripotent Stem Cells ResearchDevelopmental Biology and Gene RegulationFibroblast Growth Factor Research

Lineage Establishment and Progression within the Inner Cell Mass of the Mouse Blastocyst Requires FGFR1 and FGFR2

Open access
Kang, Minjung, Garg, Vidur, Hadjantonakis, Anna-Katerina·2017·Developmental Cell
DOI 10.1016/j.devcel.2017.05.003PMC PMC5530874
Open this paper in CoChat — free accountOpen PDF

Abstract

Fibroblast growth factor 4 (FGF4) is the key signal driving specification of primitive endoderm (PrE) versus pluripotent epiblast (EPI) within the inner cell mass (ICM) of the mouse blastocyst. To gain insight into the receptor(s) responding to FGF4 within ICM cells, we combined single-cell-resolution quantitative imaging with single-cell transcriptomics of wild-type and Fgf receptor (Fgfr) mutant embryos. Despite the PrE-specific expression of FGFR2, it is FGFR1, expressed by all ICM cells, that is critical for establishment of a PrE identity. Signaling through FGFR1 is also required to constrain levels of the pluripotency-associated factor NANOG in EPI cells. However, the activity of both receptors is required for lineage establishment within the ICM. Gene expression profiling of 534 single ICM cells identified distinct downstream targets associated with each receptor. These data lead us to propose a model whereby unique and additive activities of FGFR1 and FGFR2 within the ICM coordinate establishment of two distinct lineages.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.devcel.2017.05.003

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Mouse mutants in Fgfr1 and Fgfr2 phenocopy embryos lacking Fgf4, with defects in PrE specification and exit from naïve pluripotency in EPI.

    “Mouse mutants in both Fgfr1 and Fgfr2 phenocopy embryos lacking Fgf4, with defects in PrE specification and exit from naïve pluripotency in the EPI26,27,29.”

    From The emergent landscape of the mouse gut endoderm at single-cell resolution (2019) · cites this paper as [27]

  • 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.”

    From The emergent landscape of the mouse gut endoderm at single-cell resolution (2019) · cites this paper as [27]

  • 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.”

    From The emergent landscape of the mouse gut endoderm at single-cell resolution (2019) · cites this paper as [27]

    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

Self-check

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

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 65 · Cited by 174

Research works printed but not linked: 59

  1. Artus J Panthier JJ Hadjantonakis AK 2010 A role for PDGF signaling in expansion of the extra-embryonic endoderm lineage of the mouse blastocyst Development 137 3361 72 10.1242/dev.050864 20826533 PMC2947752 · DOI
  2. Artus J Piliszek A Hadjantonakis AK 2011 The primitive endoderm lineage of the mouse blastocyst: sequential transcription factor activation and regulation of differentiation by Sox17 Dev Biol 350 393 404 10.1016/j.ydbio.2010.12.007 21146513 PMC3461954 · DOI · Paper page
  3. Behringer R Gertsenstein M Nagy KV Nagy A 2014 Manipulating the Mouse Embryo: A Laboratory Manual 4 Cold Spring Harbor Laboratory Press Cold Spring harbor, NY
  4. Bessonnard S De Mot L Gonze D Barriol M Dennis C Goldbeter A Dupont G Chazaud C 2014 Gata6, Nanog and Erk signaling control cell fate in the inner cell mass through a tristable regulatory network Development 141 3637 48 10.1242/dev.109678 25209243 · DOI
  5. Boroviak T Loos R Lombard P Okahara J Behr R Sasaki E Nichols J Smith A Bertone P 2015 Lineage-Specific Profiling Delineates the Emergence and Progression of Naive Pluripotency in Mammalian Embryogenesis Dev Cell 35 366 82 10.1016/j.devcel.2015.10.011 26555056 PMC4643313 · DOI
  6. Boroviak T Nichols J 2017 Primate embryogenesis predicts the hallmarks of human naïve pluripotency Development 144 175 186 10.1242/dev.145177 28096211 PMC5430762 · DOI
  7. Brewer JR Mazot P Soriano P 2016 Genetic insights into the mechanisms of Fgf signaling Genes Dev 30 751 71 10.1101/gad.277137.115 27036966 PMC4826393 · DOI
  8. Brewer JR Molotkov A Mazot P Hoch RV Soriano P 2015 Fgfr1 regulates development through the combinatorial use of signaling proteins Genes Dev 29 1863 74 10.1101/gad.264994.115 26341559 PMC4573858 · DOI
  9. Buday L Warne PH Downward J 1995 Downregulation of the Ras activation pathway by MAP kinase phosphorylation of Sos Oncogene 11 1327 31 7478553
  10. Burton A Muller J Tu S Padilla-Longoria P Guccione E Torres-Padilla ME 2013 Single-Cell Profiling of Epigenetic Modifiers Identifies PRDM14 as an Inducer of Cell Fate in the Mammalian Embryo Cell Rep 5 687 701 10.1016/j.celrep.2013.09.044 24183668 · DOI
  11. Chambers I Colby D Robertson M Nichols J Lee S Tweedie S Smith A 2003 Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells Cell 113 643 55 10.1016/S0092-8674(03)00392-1 12787505 · DOI
  12. Chazaud C Yamanaka Y 2016 Lineage specification in the mouse preimplantation embryo Development 143 1063 74 10.1242/dev.128314 27048685 · DOI · Paper page
  13. Chazaud C Yamanaka Y Pawson T Rossant J 2006 Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway Dev Cell 10 615 24 10.1016/j.devcel.2006.02.020 16678776 · DOI · Paper page
  14. Dailey L Ambrosetti D Mansukhani A Basilico C 2005 Mechanisms underlying differential responses to FGF signaling Cytokine Growth Factor Rev 16 233 47 10.1016/j.cytogfr.2005.01.007 15863038 · DOI
  15. Deng CX Wynshaw-Boris A Shen MM Daugherty C Ornitz DM Leder P 1994 Murine FGFR-1 is required for early postimplantation growth and axial organization Genes Dev 8 3045 57 10.1101/gad.8.24.3045 8001823 · DOI
  16. Ekerot M Stavridis MP Delavaine L Mitchell MP Staples C Owens DM Keenan ID Dickinson RJ Storey KG Keyse SM 2008 Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter Biochem J 412 287 98 10.1042/BJ20071512 18321244 PMC2474557 · DOI
  17. Feldman B Poueymirou W Papaioannou VE DeChiara TM Goldfarb M 1995 Requirement of FGF-4 for postimplantation mouse development Science 267 246 9 7809630
  18. Ferrell JE Machleder EM 1998 The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes Science 280 895 8 10.1126/science.280.5365.895 9572732 · DOI · Paper page
  19. Frankenberg S Gerbe F Bessonnard S Belville C Pouchin P Bardot O Chazaud C 2011 Primitive endoderm differentiates via a three-step mechanism involving Nanog and RTK signaling Dev Cell 21 1005 13 10.1016/j.devcel.2011.10.019 22172669 · DOI
  20. Gerbe F Cox B Rossant J Chazaud C 2008 Dynamic expression of Lrp2 pathway members reveals progressive epithelial differentiation of primitive endoderm in mouse blastocyst Dev Biol 313 594 602 10.1016/j.ydbio.2007.10.048 18083160 · DOI
  21. Graham SJL Wicher KB Jedrusik A Guo G Herath W Robson P Zernicka-Goetz M 2014 BMP signalling regulates the pre-implantation development of extra-embryonic cell lineages in the mouse embryo Nat Commun 5 5667 10.1038/ncomms6667 25514175 PMC4338527 · DOI
  22. Guo G Huss M Tong GQ Wang C Li Sun L Clarke ND Robson P 2010 Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst Dev Cell 18 675 85 10.1016/j.devcel.2010.02.012 20412781 · DOI
  23. Herriges JC Verheyden JM Zhang Z Sui P Zhang Y Anderson MJ Swing DA Zhang Y Lewandoski M Sun X 2015 FGF-Regulated ETV Transcription Factors Control FGF-SHH Feedback Loop in Lung Branching Dev Cell 35 322 32 10.1016/j.devcel.2015.10.006 26555052 PMC4763945 · DOI
  24. Kang M Piliszek A Artus J Hadjantonakis AK 2013 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 79 10.1242/dev.084996 23193166 PMC3597205 · DOI · Paper page
  25. Kholodenko BN 2006 Cell-signalling dynamics in time and space Nat Rev Mol Cell Biol 7 165 76 10.1038/nrm1838 16482094 PMC1679905 · DOI · Paper page
  26. Kim HJ Bar-Sagi D 2004 Modulation of signalling by Sprouty: a developing story Nat Rev Mol Cell Biol 5 441 50 10.1038/nrm1400 15173823 · DOI
  27. Krawchuk D Honma-Yamanaka N Anani S Yamanaka Y 2013 FGF4 is a limiting factor controlling the proportions of primitive endoderm and epiblast in the ICM of the mouse blastocyst Dev Biol 384 65 71 10.1016/j.ydbio.2013.09.023 24063807 · DOI
  28. Kurimoto K Yabuta Y Ohinata Y Ono Y Uno KD Yamada RG Ueda HR Saitou M 2006 An improved single-cell cDNA amplification method for efficient high-density oligonucleotide microarray analysis Nucleic Acids Res 34 e42 10.1093/nar/gkl050 16547197 PMC1409679 · DOI
  29. Lanner F Rossant J 2010 The role of FGF/Erk signaling in pluripotent cells Development 137 3351 60 10.1242/dev.050146 20876656 · DOI
  30. Lemmon MA Schlessinger J 2010 Cell signaling by receptor tyrosine kinases Cell 141 1117 34 10.1016/j.cell.2010.06.011 20602996 PMC2914105 · DOI · Paper page
  31. Lesokhin aM Yu SY Katz J Baker NE 1999 Several levels of EGF receptor signaling during photoreceptor specification in wild-type, Ellipse, and null mutant Drosophila Dev Biol 205 129 44 10.1006/dbio.1998.9121 9882502 · DOI
  32. Lou X Kang M Xenopoulos P Muñoz-Descalzo S Hadjantonakis AK 2014 A rapid and efficient 2D/3D nuclear segmentation method for analysis of early mouse embryo and stem cell image data Stem cell reports 2 382 97 10.1016/j.stemcr.2014.01.010 24672759 PMC3964288 · DOI
  33. Mackeigan JP Murphy LO Dimitri Ca Blenis J 2005 Graded mitogen-activated protein kinase activity precedes switch-like c-Fos induction in mammalian cells Mol Cell Biol 25 4676 82 10.1128/MCB.25.11.4676-4682.2005 15899869 PMC1140635 · DOI
  34. Morris Sa Graham SJL Jedrusik A Zernicka-Goetz M 2013 The differential response to Fgf signalling in cells internalized at different times influences lineage segregation in preimplantation mouse embryos Open Biol 3 130104 10.1098/rsob.130104 24258274 PMC3843820 · DOI
  35. Nichols J Silva J Roode M Smith A 2009 Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo Development 136 3215 22 10.1242/dev.038893 19710168 PMC2739140 · DOI
  36. Ohnishi Y Huber W Tsumura A Kang M Xenopoulos P Kurimoto K Oleś AK Araúzo-Bravo MJ Saitou M Hadjantonakis AK Hiiragi T 2014 Cell-to-cell expression variability followed by signal reinforcement progressively segregates early mouse lineages Nat Cell Biol 16 27 37 10.1038/ncb2881 24292013 PMC4062977 · DOI · Paper page
  37. Osorno R Chambers I 2011 Transcription factor heterogeneity and epiblast pluripotency Philos Trans R Soc Lond B Biol Sci 366 2230 7 10.1098/rstb.2011.0043 21727128 PMC3130424 · DOI
  38. Owens DM Keyse SM 2007 Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases Oncogene 26 3203 13 10.1038/sj.onc.1210412 17496916 · DOI · Paper page
  39. Plusa B Piliszek A Frankenberg S Artus J Hadjantonakis AK 2008 Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst Development 135 3081 91 10.1242/dev.021519 18725515 PMC2768606 · DOI · Paper page
  40. Reyes de Mochel NS Luong M Chiang M Javier AL Luu E Toshihiko F MacGregor GR Cinquin O Cho KWY 2015 BMP signaling is required for cell cleavage in preimplantation-mouse embryos Dev Biol 397 45 55 10.1016/j.ydbio.2014.10.001 25446538 PMC4309750 · DOI
  41. Saiz N Kang M Schrode N Lou X Hadjantonakis A-K 2016 Quantitative Analysis of Protein Expression to Study Lineage Specification in Mouse Preimplantation Embryos J Vis Exp 53654 10.3791/53654 26967230 PMC4828170 · DOI
  42. Saiz N Williams KM Seshan VE Hadjantonakis AK 2016 Asynchronous fate decisions by single cells collectively ensure consistent lineage composition in the mouse blastocyst Nat Commun 7 13463 10.1038/ncomms13463 27857135 PMC5120222 · DOI
  43. Sakai K Miyazaki Ji 1997 A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission Biochem Biophys Res Commun 237 318 24 10.1006/bbrc.1997.7111 9268708 · DOI
  44. Schrode N Saiz N Di Talia S Hadjantonakis AK 2014 GATA6 levels modulate primitive endoderm cell fate choice and timing in the mouse blastocyst Dev Cell 29 454 67 10.1016/j.devcel.2014.04.011 24835466 PMC4103658 · DOI · Paper page
  45. Schrode N Xenopoulos P Piliszek A Frankenberg S Plusa B Hadjantonakis AK 2013 Anatomy of a blastocyst: cell behaviors driving cell fate choice and morphogenesis in the early mouse embryo Genesis 51 219 33 10.1002/dvg.22368 23349011 PMC3633705 · DOI
  46. Schröter C Rué P Mackenzie JP Martinez Arias A 2015 FGF/MAPK signaling sets the switching threshold of a bistable circuit controlling cell fate decisions in embryonic stem cells Development 142 4205 16 10.1242/dev.127530 26511924 PMC4689219 · DOI
  47. Shindo Y Iwamoto K Mouri K Hibino K Tomita M Kosako H Sako Y Takahashi K 2016 Conversion of graded phosphorylation into switch-like nuclear translocation via autoregulatory mechanisms in ERK signalling Nat Commun 7 10485 10.1038/ncomms10485 26786866 PMC4736105 · DOI
  48. Singh AM Hamazaki T Hankowski KE Terada N 2007 A heterogeneous expression pattern for Nanog in embryonic stem cells Stem Cells 25 2534 42 10.1634/stemcells.2007-0126 17615266 · DOI
  49. Smith A 2017 Formative pluripotency: the executive phase in a developmental continuum Development 144 365 373 10.1242/dev.142679 28143843 PMC5430734 · DOI
  50. Solter D Knowles BB 1975 Immunosurgery of mouse blastocyst Proc Natl Acad Sci U S A 72 5099 102 10.1073/pnas.72.12.5099 1108013 PMC388883 · DOI
  51. Tanaka S Kunath T Hadjantonakis AK Nagy A Rossant J 1998 Promotion of trophoblast stem cell proliferation by FGF4 Science 282 2072 5 10.1126/science.282.5396.2072 9851926 · DOI
  52. Vasudevan HN Soriano P 2016 A Thousand and One Receptor Tyrosine Kinases Current Topics in Developmental Biology Elsevier Inc 393 404 10.1016/bs.ctdb.2015.10.016 PMC4789772 26969991 · DOI
  53. Wasylyk B Hagman J Gutierrez-Hartmann A 1998 Ets transcription factors: nuclear effectors of the Ras-MAP-kinase signaling pathway Trends Biochem Sci 23 213 6 10.1016/S0968-0004(98)01211-0 9644975 · DOI
  54. Xu X Qiao W Li C Deng CX 2002 Generation of Fgfr1 conditional knockout mice Genesis 32 85 6 10.1002/gene.10028 11857785 · DOI
  55. Yamaguchi TP Harpal K Henkemeyer M Rossant J 1994 fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation Genes Dev 8 3032 44 10.1101/gad.8.24.3032 8001822 · DOI
  56. Yamanaka Y Lanner F Rossant J 2010 FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst Development 137 715 24 10.1242/dev.043471 20147376 · DOI
  57. Yang L Baker NE 2003 Cell cycle withdrawal, progression, and cell survival regulation by EGFR and its effectors in the differentiating Drosophila eye Dev Cell 4 359 69 10.1016/S1534-5807(03)00059-5 12636917 · DOI
  58. Yu K Xu J Liu Z Sosic D Shao J Olson EN Towler DA Ornitz DM 2003 Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth Development 130 3063 74 10.1242/dev.00491 12756187 · DOI
  59. Zhang J Li L 2005 BMP signaling and stem cell regulation Dev Biol 284 1 11 10.1016/j.ydbio.2005.05.009 15963490 · DOI

Authors
Kang, M., Garg, V., & Hadjantonakis, A.-K.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Hadjantonakis, Anna-Katerina
ORCID
Venue
Developmental Cell
Publisher
Elsevier BV
Published
2017-06
Volume
41
Issue
5
Pages
496-510.e5
ISSN
1534-5807 (ISSN-L)
DOI
10.1016/j.devcel.2017.05.003
PMC
PMC5530874
OpenAlex
W2619140115
Cited by
174
References
65
Citations by year
2026: 14 · 2025: 16 · 2024: 16 · 2023: 20 · 2022: 20 · 2021: 17 · 2020: 17 · 2019: 15 · 2018: 28 · 2017: 11
FWCI
7.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Developmental Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (R01-DK084391, P30-CA008748)
  • NYSTEM (C029568)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
Keywords
FGFR1, FGFR2, FGF4, inner cell mass, blastocyst, primitive endoderm, epiblast, lineage specification, Nanog, pluripotency, FGF signaling, single-cell transcriptomics, single-cell imaging, mouse embryo
MeSH terms
Animals, Cells, Cultured, Embryo, Mammalian, Endoderm, Female, Humans, Mice, Knockout, Cell Lineage, Mice, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Fibroblast Growth Factor 4, Blastocyst Inner Cell Mass

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review