Cellular and Molecular Life Sciences

, Volume 71, Issue 17, pp 3327–3338 | Cite as

A close look at the mammalian blastocyst: epiblast and primitive endoderm formation

  • Jérôme Artus
  • Claire ChazaudEmail author


During early development, the mammalian embryo undergoes a series of profound changes that lead to the formation of two extraembryonic tissues—the trophectoderm and the primitive endoderm. These tissues encapsulate the pluripotent epiblast at the time of implantation. The current model proposes that the formation of these lineages results from two consecutive binary cell fate decisions. The first controls the formation of the trophectoderm and the inner cell mass, and the second controls the formation of the primitive endoderm and the epiblast within the inner cell mass. While early mammalian embryos develop with extensive plasticity, the embryonic pattern prior to implantation is remarkably reproducible. Here, we review the molecular mechanisms driving the cell fate decision between primitive endoderm and epiblast in the mouse embryo and integrate data from recent studies into the current model of the molecular network regulating the segregation between these lineages and their subsequent differentiation.


Blastocyst Mouse embryo Cell fate specification Cell differentiation Epiblast Primitive endoderm Inner cell mass 



We thank Karel Liem and Michel Cohen-Tannoudji for critical reading of the manuscript. JA is supported by the European programme Marie Curie (International Incoming Fellowship, 7th European Community Framework Programme), the Institut Pasteur, the CNRS and the ANR “Laboratoire d’Excellence” programme (REVIVE, ANR-10-LABX-73-01). CC is supported by the ANR EpiNodal and ARC (PJA 20131200380).


  1. 1.
    Beddington RS, Robertson EJ (1999) Axis development and early asymmetry in mammals. Cell 96(2):195–209PubMedCrossRefGoogle Scholar
  2. 2.
    Arnold SJ, Robertson EJ (2009) Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nat Rev Mol Cell Biol 10(2):91–103. doi: 10.1038/nrm2618 PubMedCrossRefGoogle Scholar
  3. 3.
    Artus J, Cohen-Tannoudji M (2008) Cell cycle regulation during early mouse embryogenesis. Mol Cell Endocrinol 282(1–2):78–86. doi: 10.1016/j.mce.2007.11.008 PubMedCrossRefGoogle Scholar
  4. 4.
    Flach G, Johnson MH, Braude PR, Taylor RA, Bolton VN (1982) The transition from maternal to embryonic control in the 2-cell mouse embryo. EMBO J 1(6):681–686PubMedCentralPubMedGoogle Scholar
  5. 5.
    Bouniol C, Nguyen E, Debey P (1995) Endogenous transcription occurs at the 1-cell stage in the mouse embryo. Exp Cell Res 218(1):57–62. doi: 10.1006/excr.1995.1130 PubMedCrossRefGoogle Scholar
  6. 6.
    Yamanaka Y, Ralston A, Stephenson RO, Rossant J (2006) Cell and molecular regulation of the mouse blastocyst. Dev Dyn 235(9):2301–2314PubMedCrossRefGoogle Scholar
  7. 7.
    Dard N, Breuer M, Maro B, Louvet-Vallee S (2008) Morphogenesis of the mammalian blastocyst. Mol Cell Endocrinol 282(1–2):70–77PubMedCrossRefGoogle Scholar
  8. 8.
    Johnson MH (2009) From mouse egg to mouse embryo: polarities, axes, and tissues. Annu Rev Cell Dev Biol 25:483–512. doi: 10.1146/annurev.cellbio.042308.113348 PubMedCrossRefGoogle Scholar
  9. 9.
    Eckert JJ, Fleming TP (2008) Tight junction biogenesis during early development. Biochim Biophys Acta 1778(3):717–728. doi: 10.1016/j.bbamem.2007.09.031 PubMedCrossRefGoogle Scholar
  10. 10.
    Kwon GS, Viotti M, Hadjantonakis AK (2008) The endoderm of the mouse embryo arises by dynamic widespread intercalation of embryonic and extraembryonic lineages. Dev Cell 15(4):509–520PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Stephenson RO, Rossant J, Tam PP (2012) Intercellular interactions, position, and polarity in establishing blastocyst cell lineages and embryonic axes. Cold Spring Harb Perspect Biol. doi: 10.1101/cshperspect.a008235 PubMedGoogle Scholar
  12. 12.
    Rossant J, Chazaud C, Yamanaka Y (2003) Lineage allocation and asymmetries in the early mouse embryo. Philos Trans R Soc Lond B Biol Sci 358(1436):1341–1348 (discussion 1349)PubMedCentralPubMedCrossRefGoogle Scholar
  13. 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(5):615–624. doi: 10.1016/j.devcel.2006.02.020 PubMedCrossRefGoogle Scholar
  14. 14.
    Dietrich JE, Hiiragi T (2007) Stochastic patterning in the mouse pre-implantation embryo. Development 134(23):4219–4231PubMedCrossRefGoogle Scholar
  15. 15.
    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(18):3081–3091PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    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(4):675–685. doi: 10.1016/j.devcel.2010.02.012 PubMedCrossRefGoogle Scholar
  17. 17.
    Miyanari Y, Torres-Padilla ME (2012) Control of ground-state pluripotency by allelic regulation of Nanog. Nature 483(7390):470–473. doi: 10.1038/nature10807 PubMedCrossRefGoogle Scholar
  18. 18.
    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(5):e42PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    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(2):594–602PubMedCrossRefGoogle Scholar
  20. 20.
    Ohnishi Y, Huber W, Tsumura A, Kang M, Xenopoulos P, Kurimoto K, Oles AK, Arauzo-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(1):27–37. doi: 10.1038/ncb2881 PubMedCentralPubMedGoogle Scholar
  21. 21.
    Chambers I, Silva J, Colby D, Nichols J, Nijmeijer B, Robertson M, Vrana J, Jones K, Grotewold L, Smith A (2007) Nanog safeguards pluripotency and mediates germline development. Nature 450(7173):1230–1234PubMedCrossRefGoogle Scholar
  22. 22.
    Canham MA, Sharov AA, Ko MS, Brickman JM (2010) Functional heterogeneity of embryonic stem cells revealed through translational amplification of an early endodermal transcript. PLoS Biol 8(5):e1000379. doi: 10.1371/journal.pbio.1000379 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Kalmar T, Lim C, Hayward P, Munoz-Descalzo S, Nichols J, Garcia-Ojalvo J, Martinez Arias A (2009) Regulated fluctuations in nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biol 7(7):e1000149. doi: 10.1371/journal.pbio.1000149 PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Navarro P, Festuccia N, Colby D, Gagliardi A, Mullin NP, Zhang W, Karwacki-Neisius V, Osorno R, Kelly D, Robertson M, Chambers I (2012) OCT4/SOX2-independent Nanog autorepression modulates heterogeneous Nanog gene expression in mouse ES cells. EMBO J 31(24):4547–4562. doi: 10.1038/emboj.2012.321 PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Fidalgo M, Faiola F, Pereira CF, Ding J, Saunders A, Gingold J, Schaniel C, Lemischka IR, Silva JC, Wang J (2012) Zfp281 mediates Nanog autorepression through recruitment of the NuRD complex and inhibits somatic cell reprogramming. Proc Natl Acad Sci USA 109(40):16202–16207. doi: 10.1073/pnas.1208533109 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Gasnier M, Dennis C, Vaurs-Barriere C, Chazaud C (2013) Fluorescent mRNA labeling through cytoplasmic FISH. Nat Protoc 8(12):2538–2547. doi: 10.1038/nprot.2013.160 PubMedCrossRefGoogle Scholar
  27. 27.
    Arman E, Haffner-Krausz R, Chen Y, Heath JK, Lonai P (1998) Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development. Proc Natl Acad Sci USA 95(9):5082–5087PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Feldman B, Poueymirou W, Papaioannou VE, DeChiara TM, Goldfarb M (1995) Requirement of FGF-4 for postimplantation mouse development. Science 267(5195):246–249PubMedCrossRefGoogle Scholar
  29. 29.
    Goldin SN, Papaioannou VE (2003) Paracrine action of FGF4 during periimplantation development maintains trophectoderm and primitive endoderm. Genesis 36(1):40–47PubMedCrossRefGoogle Scholar
  30. 30.
    Wilder PJ, Kelly D, Brigman K, Peterson CL, Nowling T, Gao QS, McComb RD, Capecchi MR, Rizzino A (1997) Inactivation of the FGF-4 gene in embryonic stem cells alters the growth and/or the survival of their early differentiated progeny. Dev Biol 192(2):614–629PubMedCrossRefGoogle Scholar
  31. 31.
    Cheng AM, Saxton TM, Sakai R, Kulkarni S, Mbamalu G, Vogel W, Tortorice CG, Cardiff RD, Cross JC, Muller WJ, Pawson T (1998) Mammalian Grb2 regulates multiple steps in embryonic development and malignant transformation. Cell 95(6):793–803PubMedCrossRefGoogle Scholar
  32. 32.
    Chen Y, Li X, Eswarakumar VP, Seger R, Lonai P (2000) Fibroblast growth factor (FGF) signaling through PI 3-kinase and Akt/PKB is required for embryoid body differentiation. Oncogene 19(33):3750–3756. doi: 10.1038/sj.onc.1203726 PubMedCrossRefGoogle Scholar
  33. 33.
    Nichols J, Silva J, Roode M, Smith A (2009) Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development 136(19):3215–3222PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Yamanaka Y, Lanner F, Rossant J (2010) FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst. Development 137(5):715–724. doi: 10.1242/dev.043471 PubMedCrossRefGoogle Scholar
  35. 35.
    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(2):267–279. doi: 10.1242/dev.084996 PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    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. doi: 10.1016/j.ydbio.2013.09.023 PubMedGoogle Scholar
  37. 37.
    Lanner F, Lee KL, Sohl M, Holmborn K, Yang H, Wilbertz J, Poellinger L, Rossant J, Farnebo F (2010) Heparan sulfation-dependent fibroblast growth factor signaling maintains embryonic stem cells primed for differentiation in a heterogeneous state. Stem Cells 28(2):191–200. doi: 10.1002/stem.265 PubMedGoogle Scholar
  38. 38.
    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(6):1005–1013. doi: 10.1016/j.devcel.2011.10.019 PubMedCrossRefGoogle Scholar
  39. 39.
    Fujikura J, Yamato E, Yonemura S, Hosoda K, Masui S, Nakao K, Miyazaki Ji J, Niwa H (2002) Differentiation of embryonic stem cells is induced by GATA factors. Genes Dev 16(7):784–789PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Shimosato D, Shiki M, Niwa H (2007) Extra-embryonic endoderm cells derived from ES cells induced by GATA factors acquire the character of XEN cells. BMC Dev Biol 7:80PubMedCentralPubMedGoogle Scholar
  41. 41.
    Singh AM, Hamazaki T, Hankowski KE, Terada N (2007) A heterogeneous expression pattern for Nanog in embryonic stem cells. Stem Cells 25(10):2534–2542. doi: 10.1634/stemcells.2007-0126 PubMedCrossRefGoogle Scholar
  42. 42.
    Filipczyk A, Gkatzis K, Fu J, Hoppe PS, Lickert H, Anastassiadis K, Schroeder T (2013) Biallelic expression of nanog protein in mouse embryonic stem cells. Cell Stem Cell 13(1):12–13. doi: 10.1016/j.stem.2013.04.025 PubMedCrossRefGoogle Scholar
  43. 43.
    Faddah DA, Wang H, Cheng AW, Katz Y, Buganim Y, Jaenisch R (2013) Single-cell analysis reveals that expression of nanog is biallelic and equally variable as that of other pluripotency factors in mouse ESCs. Cell Stem Cell 13(1):23–29. doi: 10.1016/j.stem.2013.04.019 PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Deng Q, Ramskold D, Reinius B, Sandberg R (2014) Single-cell RNA-seq reveals dynamic, random monoallelic gene expression in mammalian cells. Science 343(6167):193–196. doi: 10.1126/science.1245316 PubMedCrossRefGoogle Scholar
  45. 45.
    Grabarek JB, Zyzynska K, Saiz N, Piliszek A, Frankenberg S, Nichols J, Hadjantonakis AK, Plusa B (2012) Differential plasticity of epiblast and primitive endoderm precursors within the ICM of the early mouse embryo. Development 139(1):129–139. doi: 10.1242/dev.067702 PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Frum T, Halbisen MA, Wang C, Amiri H, Robson P, Ralston A (2013) Oct4 cell-autonomously promotes primitive endoderm development in the mouse blastocyst. Dev Cell 25(6):610–622. doi: 10.1016/j.devcel.2013.05.004 PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Le Bin GC, Munoz-Descalzo S, Kurowski A, Leitch H, Lou X, Mansfield W, Etienne-Dumeau C, Grabole N, Mulas C, Niwa H, Hadjantonakis AK, Nichols J (2014) Oct4 is required for lineage priming in the developing inner cell mass of the mouse blastocyst. Development 141(5):1001–1010. doi: 10.1242/dev.096875 PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Brumbaugh J, Hou Z, Russell JD, Howden SE, Yu P, Ledvina AR, Coon JJ, Thomson JA (2012) Phosphorylation regulates human OCT4. Proc Natl Acad Sci USA 109(19):7162–7168. doi: 10.1073/pnas.1203874109 PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Saxe JP, Tomilin A, Scholer HR, Plath K, Huang J (2009) Post-translational regulation of Oct4 transcriptional activity. PLoS One 4(2):e4467. doi: 10.1371/journal.pone.0004467 PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Plachta N, Bollenbach T, Pease S, Fraser SE, Pantazis P (2011) Oct4 kinetics predict cell lineage patterning in the early mammalian embryo. Nat Cell Biol 13(2):117–123. doi: 10.1038/ncb2154 PubMedGoogle Scholar
  51. 51.
    Kaur G, Costa MW, Nefzger CM, Silva J, Fierro-Gonzalez JC, Polo JM, Bell TD, Plachta N (2013) Probing transcription factor diffusion dynamics in the living mammalian embryo with photoactivatable fluorescence correlation spectroscopy. Nat Commun 4:1637. doi: 10.1038/ncomms2657 PubMedCrossRefGoogle Scholar
  52. 52.
    Arias AM, Nichols J, Schroter C (2013) A molecular basis for developmental plasticity in early mammalian embryos. Development 140(17):3499–3510. doi: 10.1242/dev.091959 CrossRefGoogle Scholar
  53. 53.
    Meilhac SM, Adams RJ, Morris SA, Danckaert A, Le Garrec JF, Zernicka-Goetz M (2009) Active cell movements coupled to positional induction are involved in lineage segregation in the mouse blastocyst. Dev Biol 331(2):210–221PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Morris SA, Teo RT, Li H, Robson P, Glover DM, Zernicka-Goetz M (2010) Origin and formation of the first two distinct cell types of the inner cell mass in the mouse embryo. Proc Natl Acad Sci USA 107(14):6364–6369PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Morris SA, Guo Y, Zernicka-Goetz M (2012) Developmental plasticity is bound by pluripotency and the Fgf and Wnt signaling pathways. Cell Rep 2(4):756–765. doi: 10.1016/j.celrep.2012.08.029 PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    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(20):3361–3372. doi: 10.1242/dev.050864 PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Artus J, Piliszek A, Hadjantonakis A-K (2011) The primitive endoderm lineage of the mouse blastocyst: sequential transcription factor activation and regulation of differentiation by Sox17. Dev Biol 350(2):393–404. doi: 10.1016/j.ydbio.2010.12.007 PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Batlle-Morera L, Smith A, Nichols J (2008) Parameters influencing derivation of embryonic stem cells from murine embryos. Genesis 46(12):758–767. doi: 10.1002/dvg.20442 PubMedCrossRefGoogle Scholar
  59. 59.
    Morris SA, Graham SJ, 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(11):130104. doi: 10.1098/rsob.130104 PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Krupa M, Mazur E, Szczepanska K, Filimonow K, Maleszewski M, Suwinska A (2013) Allocation of inner cells to epiblast vs primitive endoderm in the mouse embryo is biased but not determined by the round of asymmetric divisions (8–>16- and 16–>32-cells). Dev Biol. doi: 10.1016/j.ydbio.2013.09.008 PubMedGoogle Scholar
  61. 61.
    Niakan KK, Ji H, Maehr R, Vokes SA, Rodolfa KT, Sherwood RI, Yamaki M, Dimos JT, Chen AE, Melton DA, McMahon AP, Eggan K (2010) Sox17 promotes differentiation in mouse embryonic stem cells by directly regulating extraembryonic gene expression and indirectly antagonizing self-renewal. Genes Dev 24(3):312–326. doi: 10.1101/gad.1833510 PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Messerschmidt DM, Kemler R (2010) Nanog is required for primitive endoderm formation through a non-cell autonomous mechanism. Dev Biol 344(1):129–137. doi: 10.1016/j.ydbio.2010.04.020 PubMedCrossRefGoogle Scholar
  63. 63.
    Aksoy I, Jauch R, Eras V, Bin AC, Chen J, Divakar U, Ng CK, Kolatkar PR, Stanton LW (2013) Sox transcription factors require selective interactions with Oct4 and specific transactivation functions to mediate reprogramming. Stem Cells. doi: 10.1002/stem.1522 PubMedGoogle Scholar
  64. 64.
    Niwa H, Miyazaki J, Smith AG (2000) Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet 24(4):372–376PubMedCrossRefGoogle Scholar
  65. 65.
    Radzisheuskaya A, Chia Gle B, dos Santos RL, Theunissen TW, Castro LF, Nichols J, Silva JC (2013) A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages. Nat Cell Biol 15(6):579–590. doi: 10.1038/ncb2742 PubMedCentralPubMedGoogle Scholar
  66. 66.
    Do DV, Ueda J, Messerschmidt DM, Lorthongpanich C, Zhou Y, Feng B, Guo G, Lin PJ, Hossain MZ, Zhang W, Moh A, Wu Q, Robson P, Ng HH, Poellinger L, Knowles BB, Solter D, Fu XY (2013) A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo. Genes Dev 27(12):1378–1390. doi: 10.1101/gad.221176.113 PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Kunath T, Saba-El-Leil MK, Almousailleakh M, Wray J, Meloche S, Smith A (2007) FGF stimulation of the Erk1/2 signalling cascade triggers transition of pluripotent embryonic stem cells from self-renewal to lineage commitment. Development 134(16):2895–2902. doi: 10.1242/dev.02880 PubMedCrossRefGoogle Scholar
  68. 68.
    Coucouvanis E, Martin GR (1995) Signals for death and survival: a two-step mechanism for cavitation in the vertebrate embryo. Cell 83(2):279–287PubMedCrossRefGoogle Scholar
  69. 69.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676. doi: 10.1016/j.cell.2006.07.024 PubMedCrossRefGoogle Scholar
  70. 70.
    Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S (2008) Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26(1):101–106. doi: 10.1038/nbt1374 PubMedCrossRefGoogle Scholar
  71. 71.
    Ema M, Mori D, Niwa H, Hasegawa Y, Yamanaka Y, Hitoshi S, Mimura J, Kawabe Y, Hosoya T, Morita M, Shimosato D, Uchida K, Suzuki N, Yanagisawa J, Sogawa K, Rossant J, Yamamoto M, Takahashi S, Fujii-Kuriyama Y (2008) Krüppel-like factor 5 is essential for blastocyst development and the normal self-renewal of mouse ESCs. Cell Stem Cell 3(5):555–567. doi: 10.1016/j.stem.2008.09.003 PubMedCrossRefGoogle Scholar
  72. 72.
    Lin SC, Wani MA, Whitsett JA, Wells JM (2010) Klf5 regulates lineage formation in the pre-implantation mouse embryo. Development 137(23):3953–3963. doi: 10.1242/dev.054775 PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    Saiz N, Grabarek JB, Sabherwal N, Papalopulu N, Plusa B (2013) Atypical protein kinase C couples cell sorting with primitive endoderm maturation in the mouse blastocyst. Development 140(21):4311–4322. doi: 10.1242/dev.093922 PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Townes P, Holfreter J (1955) Directed movements and selective adhesion of embryonic amphibian cells. J Exp Zool 128:53–120CrossRefGoogle Scholar
  75. 75.
    Yang DH, Smith ER, Roland IH, Sheng Z, He J, Martin WD, Hamilton TC, Lambeth JD, Xu XX (2002) Disabled-2 is essential for endodermal cell positioning and structure formation during mouse embryogenesis. Dev Biol 251(1):27–44PubMedCrossRefGoogle Scholar
  76. 76.
    Liu J, He X, Corbett SA, Lowry SF, Graham AM, Fassler R, Li S (2009) Integrins are required for the differentiation of visceral endoderm. J Cell Sci 122(Pt 2):233–242PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Fassler R, Pfaff M, Murphy J, Noegel AA, Johansson S, Timpl R, Albrecht R (1995) Lack of beta 1 integrin gene in embryonic stem cells affects morphology, adhesion, and migration but not integration into the inner cell mass of blastocysts. J Cell Biol 128(5):979–988PubMedCrossRefGoogle Scholar
  78. 78.
    Stephens LE, Sutherland AE, Klimanskaya IV, Andrieux A, Meneses J, Pedersen RA, Damsky CH (1995) Deletion of beta 1 integrins in mice results in inner cell mass failure and peri-implantation lethality. Genes Dev 9(15):1883–1895PubMedCrossRefGoogle Scholar
  79. 79.
    Moore R, Cai KQ, Escudero DO, Xu XX (2009) Cell adhesive affinity does not dictate primitive endoderm segregation and positioning during murine embryoid body formation. Genesis 47(9):579–589. doi: 10.1002/dvg.20536 PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Smyth N, Vatansever HS, Meyer M, Frie C, Paulsson M, Edgar D (1998) The targeted deletion of the LAMC1 gene. Ann N Y Acad Sci 857:283–286PubMedCrossRefGoogle Scholar
  81. 81.
    Krupinski P, Chickarmane V, Peterson C (2011) Simulating the mammalian blastocyst–molecular and mechanical interactions pattern the embryo. PLoS Comput Biol 7(5):e1001128. doi: 10.1371/journal.pcbi.1001128 PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Krupinski P, Chickarmane V, Peterson C (2012) Computational multiscale modeling of embryo development. Curr Opin Genet Dev 22(6):613–618. doi: 10.1016/j.gde.2012.08.006 PubMedCrossRefGoogle Scholar
  83. 83.
    Krens SF, Heisenberg CP (2011) Cell sorting in development. Curr Top Dev Biol 95:189–213. doi: 10.1016/B978-0-12-385065-2.00006-2 PubMedCrossRefGoogle Scholar
  84. 84.
    Fleming TP, Warren PD, Chisholm JC, Johnson MH (1984) Trophectodermal processes regulate the expression of totipotency within the inner cell mass of the mouse expanding blastocyst. J Embryol Exp Morphol 84:63–90PubMedGoogle Scholar
  85. 85.
    El-Shershaby AM, Hinchliffe JR (1974) Cell redundancy in the zona-intact preimplantation mouse blastocyst: a light and electron microscope study of dead cells and their fate. J Embryol Exp Morphol 31(3):643–654PubMedGoogle Scholar
  86. 86.
    Potts DM, Wilson IB (1967) The preimplantation conceptus of the mouse at 90 hours post coitum. J Anat 102(Pt 1):1–11PubMedCentralPubMedGoogle Scholar
  87. 87.
    Copp AJ (1978) Interaction between inner cell mass and trophectoderm of the mouse blastocyst. I. A study of cellular proliferation. J Embryol Exp Morphol 48:109–125PubMedGoogle Scholar
  88. 88.
    Pierce GB, Lewellyn AL, Parchment RE (1989) Mechanism of programmed cell death in the blastocyst. Proc Natl Acad Sci USA 86(10):3654–3658PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Hardy K (1997) Cell death in the mammalian blastocyst. Mol Hum Reprod 3(10):919–925PubMedCrossRefGoogle Scholar
  90. 90.
    Artus J, Kang M, Cohen-Tannoudji M, Hadjantonakis AK (2013) PDGF signaling is required for primitive endoderm cell survival in the inner cell mass of the mouse blastocyst. Stem Cells 31(9):1932–1941. doi: 10.1002/stem.1442 PubMedCrossRefGoogle Scholar
  91. 91.
    Brown K, Doss MX, Legros S, Artus J, Hadjantonakis AK, Foley AC (2010) eXtraembryonic ENdoderm (XEN) stem cells produce factors that activate heart formation. PLoS One 5(10):e13446. doi: 10.1371/journal.pone.0013446 PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Artus J, Douvaras P, Piliszek A, Isern J, Baron MH, Hadjantonakis AK (2012) BMP4 signaling directs primitive endoderm-derived XEN cells to an extraembryonic visceral endoderm identity. Dev Biol 361(2):245–262. doi: 10.1016/j.ydbio.2011.10.015 PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 78(12):7634–7638PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292(5819):154–156PubMedCrossRefGoogle Scholar
  95. 95.
    Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, Cohen P, Smith A (2008) The ground state of embryonic stem cell self-renewal. Nature 453(7194):519–523PubMedCrossRefGoogle Scholar
  96. 96.
    Hanna J, Markoulaki S, Mitalipova M, Cheng AW, Cassady JP, Staerk J, Carey BW, Lengner CJ, Foreman R, Love J, Gao Q, Kim J, Jaenisch R (2009) Metastable pluripotent states in NOD-mouse-derived ESCs. Cell Stem Cell 4(6):513–524. doi: 10.1016/j.stem.2009.04.015 PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Buehr M, Meek S, Blair K, Yang J, Ure J, Silva J, McLay R, Hall J, Ying QL, Smith A (2008) Capture of authentic embryonic stem cells from rat blastocysts. Cell 135(7):1287–1298. doi: 10.1016/j.cell.2008.12.007 PubMedCrossRefGoogle Scholar
  98. 98.
    Li P, Tong C, Mehrian-Shai R, Jia L, Wu N, Yan Y, Maxson RE, Schulze EN, Song H, Hsieh CL, Pera MF, Ying QL (2008) Germline competent embryonic stem cells derived from rat blastocysts. Cell 135(7):1299–1310. doi: 10.1016/j.cell.2008.12.006 PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Lanner F, Rossant J (2010) The role of FGF/Erk signaling in pluripotent cells. Development 137(20):3351–3360. doi: 10.1242/dev.050146 PubMedCrossRefGoogle Scholar
  100. 100.
    Sokol SY (2011) Maintaining embryonic stem cell pluripotency with Wnt signaling. Development 138(20):4341–4350. doi: 10.1242/dev.066209 PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Kelly KF, Ng DY, Jayakumaran G, Wood GA, Koide H, Doble BW (2011) Beta-catenin enhances Oct-4 activity and reinforces pluripotency through a TCF-independent mechanism. Cell Stem Cell 8(2):214–227. doi: 10.1016/j.stem.2010.12.010 PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Takao Y, Yokota T, Koide H (2007) Beta-catenin up-regulates Nanog expression through interaction with Oct-3/4 in embryonic stem cells. Biochem Biophys Res Commun 353(3):699–705PubMedCrossRefGoogle Scholar
  103. 103.
    Faunes F, Hayward P, Descalzo SM, Chatterjee SS, Balayo T, Trott J, Christoforou A, Ferrer-Vaquer A, Hadjantonakis AK, Dasgupta R, Arias AM (2013) A membrane-associated beta-catenin/Oct4 complex correlates with ground-state pluripotency in mouse embryonic stem cells. Development 140(6):1171–1183. doi: 10.1242/dev.085654 PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Yi F, Pereira L, Hoffman JA, Shy BR, Yuen CM, Liu DR, Merrill BJ (2011) Opposing effects of Tcf3 and Tcf1 control Wnt stimulation of embryonic stem cell self-renewal. Nat Cell Biol 13(7):762–770. doi: 10.1038/ncb2283 PubMedCentralPubMedGoogle Scholar
  105. 105.
    Wray J, Kalkan T, Gomez-Lopez S, Eckardt D, Cook A, Kemler R, Smith A (2011) Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation. Nat Cell Biol 13(7):838–845. doi: 10.1038/ncb2267 PubMedCentralPubMedGoogle Scholar
  106. 106.
    Ying QL, Nichols J, Chambers I, Smith A (2003) BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 115(3):281–292PubMedCrossRefGoogle Scholar
  107. 107.
    Coucouvanis E, Martin GR (1999) BMP signaling plays a role in visceral endoderm differentiation and cavitation in the early mouse embryo. Development 126(3):535–546PubMedGoogle Scholar
  108. 108.
    Keller GM (1995) In vitro differentiation of embryonic stem cells. Curr Opin Cell Biol 7(6):862–869PubMedCrossRefGoogle Scholar
  109. 109.
    Tanaka S, Kunath T, Hadjantonakis AK, Nagy A, Rossant J (1998) Promotion of trophoblast stem cell proliferation by FGF4. Science 282(5396):2072–2075PubMedCrossRefGoogle Scholar
  110. 110.
    Lu CW, Yabuuchi A, Chen L, Viswanathan S, Kim K, Daley GQ (2008) Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos. Nat Genet 40(7):921–926. doi: 10.1038/ng.173 PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Niwa H, Toyooka Y, Shimosato D, Strumpf D, Takahashi K, Yagi R, Rossant J (2005) Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 123(5):917–929PubMedCrossRefGoogle Scholar
  112. 112.
    Nishioka N, Inoue K, Adachi K, Kiyonari H, Ota M, Ralston A, Yabuta N, Hirahara S, Stephenson RO, Ogonuki N, Makita R, Kurihara H, Morin-Kensicki EM, Nojima H, Rossant J, Nakao K, Niwa H, Sasaki H (2009) The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell 16(3):398–410PubMedCrossRefGoogle Scholar
  113. 113.
    Ralston A, Cox BJ, Nishioka N, Sasaki H, Chea E, Rugg-Gunn P, Guo G, Robson P, Draper JS, Rossant J (2010) Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2. Development 137(3):395–403. doi: 10.1242/dev.038828 PubMedCrossRefGoogle Scholar
  114. 114.
    Erlebacher A, Price KA, Glimcher LH (2004) Maintenance of mouse trophoblast stem cell proliferation by TGF-beta/activin. Dev Biol 275(1):158–169. doi: 10.1016/j.ydbio.2004.07.032 PubMedCrossRefGoogle Scholar
  115. 115.
    Natale DR, Hemberger M, Hughes M, Cross JC (2009) Activin promotes differentiation of cultured mouse trophoblast stem cells towards a labyrinth cell fate. Dev Biol 335(1):120–131. doi: 10.1016/j.ydbio.2009.08.022 PubMedCrossRefGoogle Scholar
  116. 116.
    Kunath T, Arnaud D, Uy GD, Okamoto I, Chureau C, Yamanaka Y, Heard E, Gardner RL, Avner P, Rossant J (2005) Imprinted X-inactivation in extra-embryonic endoderm cell lines from mouse blastocysts. Development 132(7):1649–1661PubMedCrossRefGoogle Scholar
  117. 117.
    Brown K, Legros S, Artus J, Doss MX, Khanin R, Hadjantonakis AK, Foley A (2010) A comparative analysis of extra-embryonic endoderm cell lines. PLoS One 5(8):e12016. doi: 10.1371/journal.pone.0012016 PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Kruithof-de Julio M, Alvarez MJ, Galli A, Chu J, Price SM, Califano A, Shen MM (2011) Regulation of extra-embryonic endoderm stem cell differentiation by Nodal and Cripto signaling. Development 138(18):3885–3895. doi: 10.1242/dev.065656 PubMedCrossRefGoogle Scholar
  119. 119.
    Cho LT, Wamaitha SE, Tsai IJ, Artus J, Sherwood RI, Pedersen RA, Hadjantonakis AK, Niakan KK (2012) Conversion from mouse embryonic to extra-embryonic endoderm stem cells reveals distinct differentiation capacities of pluripotent stem cell states. Development 139(16):2866–2877. doi: 10.1242/dev.078519 PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Kuijk EW, van Tol LT, Van de Velde H, Wubbolts R, Welling M, Geijsen N, Roelen BA (2012) The roles of FGF and MAP kinase signaling in the segregation of the epiblast and hypoblast cell lineages in bovine and human embryos. Development 139(5):871–882. doi: 10.1242/dev.071688 PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Roode M, Blair K, Snell P, Elder K, Marchant S, Smith A, Nichols J (2012) Human hypoblast formation is not dependent on FGF signalling. Dev Biol 361(2):358–363. doi: 10.1016/j.ydbio.2011.10.030 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2014

Authors and Affiliations

  1. 1.Institut PasteurMouse Functional Genetics, CNRS URA2578ParisFrance
  2. 2.Clermont UniversitéLaboratoire GReD, Université d’AuvergneClermont-FerrandFrance
  3. 3.Inserm, UMR1103Clermont-FerrandFrance
  4. 4.CNRS, UMR6293Clermont-FerrandFrance

Personalised recommendations