Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Gene function in mouse embryogenesis: get set for gastrulation

Nature Reviews Genetics volume 8, pages 368–381 (2007)Cite this article

Key Points

  • At the time of implantation, the mouse embryo consists of three cell lineages: the trophectoderm, the primitive endoderm and the epiblast. The primitive endoderm forms from Gata6-expressing cells that are scattered throughout the inner cell mass. Its formation requires the action of a transcriptional network and sorting of cells, which is mediated by growth factor receptor bound protein 2 (GRB2) and mitogen-activated protein kinase (MAPK) activities.

  • The extraembryonic ectoderm, derived from the trophectoderm, is maintained by the interaction of nodal and FGF signals that originate in the epiblast. The visceral endoderm, which derives from the primitive endoderm, is initially regionalized in a proximal–distal manner by the action of nodal signalling. Some recent data indicate that asymmetry might be present in the primitive endoderm soon after it forms, but this is controversial.

  • The formation of the distal visceral endoderm requires interactions with the epiblast and extraembryonic ectoderm, through the actions of nodal, WNT and bone morphogenetic protein 4 (BMP4) signalling.

  • Formation of the primitive streak and the initiation of gastrulation require correct anterior–posterior patterning of the epiblast. This is achieved by a balance of posteriorizing signals (WNT, nodal and BMP) and their antagonists, which are produced in the anterior visceral endoderm.

  • Migration of the distal visceral endoderm to the anterior part of the embryo is driven by asymmetrical cell proliferation, which is affected by nodal and its antagonists along with active cell migration, and modulated by the level of WNT signals.

  • The formation of the mesoderm and definitive endoderm requires migration of cells through the primitive streak. This requires FGF signalling, which influences WNT signalling. Correct migration of the mesoderm and endoderm requires the actions of the transcription factors that are encoded by Lhx1 and Mixl1.

  • The choice of cells in the primitive streak to follow either a mesoderm or a definitive endoderm fate is influenced by the signalling activity of transforming growth factor-β (TGFB)-related factors and WNT. Loss of gene activity downstream of nodal signalling results in reduced potential to form endoderm.

Abstract

During early mouse embryogenesis, temporal and spatial regulation of gene expression and cell signalling influences lineage specification, embryonic polarity, the patterning of tissue progenitors and the morphogenetic movement of cells and tissues. Uniquely in mammals, the extraembryonic tissues are the source of signals for lineage specification and tissue patterning. Here we discuss recent discoveries about the lead up to gastrulation, including early manifestations of asymmetry, coordination of cell and tissue movements and the interactions of transcription factors and signalling activity for lineage allocation and germ-layer specification.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Early post-implantation development in the mouse.
Figure 2: A network of signalling activity leading to patterning of the visceral endoderm and the epiblast in the distal visceral endoderm (DVE)-stage embryo.
Figure 3: Pattern of cell movement during embryogenesis and the molecular activities that influence cell or tissue movement.
Figure 4: Gene expression and regionalized allocation of tissue progenitors in the primitive streak during gastrulation.

Similar content being viewed by others

References

  1. Lawson, K. A. Fate mapping the mouse embryo. Int. J. Dev. Biol. 43, 773–775 (1999).

    CAS  PubMed  Google Scholar 

  2. Tam, P. P. L. & Gad, J. M. Gastrulation of the mouse embryo in Gastrulation 223–262 (Cold Spring Harbor Laboratory Press, New York, 2004).

    Google Scholar 

  3. Chew, J. L. et al. Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells. Mol. Cell. Biol. 25, 6031–6046 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Okumura-Nakanishi, S., Saito, M., Niwa, H. & Ishikawa, F. Oct-3/4 and Sox2 regulate Oct-3/4 gene in embryonic stem cells. J. Biol. Chem. 280, 5307–5317 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Rodda, D. J. et al. Transcriptional regulation of nanog by OCT4 and SOX2. J. Biol. Chem. 280, 24731–24737 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Zhang, J. et al. Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nature Cell Biol. 8, 1114–1123 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Sakaki-Yumoto, M. et al. The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development. Development 133, 3005–3013 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Wu, Q. et al. Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells. J. Biol. Chem. 281, 24090–24094 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Lee, T. I. et al. Control of developmental regulators by polycomb in human embryonic stem cells. Cell 125, 301–313 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Boyer, L. A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Camus, A., Perea-Gomez, A., Moreau, A. & Collignon, J. Absence of Nodal signaling promotes precocious neural differentiation in the mouse embryo. Dev. Biol. 295, 743–755 (2006). This paper shows that the epiblast of Nodal−/− embryos prematurely differentiates into neural cell types. The data show a role for nodal in repressing anterior and neural differentiation.

    Article  CAS  PubMed  Google Scholar 

  12. Mesnard, D., Guzman-Ayala, M. & Constam, D. B. Nodal specifies embryonic visceral endoderm and sustains pluripotent cells in the epiblast before overt axial patterning. Development 133, 2497–2505 (2006). This paper demonstrates that nodal signalling is required for early proximal–distal patterning of the embryo, dividing the visceral endoderm into embryonic and extraembryonic compartments. The authors show that nodal has a role in this process before the formation of the DVE.

    CAS  PubMed  Google Scholar 

  13. James, D., Levine, A. J., Besser, D. & Hemmati-Brivanlou, A. TGFβ/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development 132, 1273–1282 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P. & Brivanlou, A. H. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature Med. 10, 55–63 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Kemler, R. et al. Stabilization of β-catenin in the mouse zygote leads to premature epithelial-mesenchymal transition in the epiblast. Development 131, 5817–5824 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Liu, P. et al. Requirement for Wnt3 in vertebrate axis formation. Nature Genet. 22, 361–365 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Lindsley, R. C., Gill, J. G., Kyba, M., Murphy, T. L. & Murphy, K. M. Canonical Wnt signaling is required for development of embryonic stem cell-derived mesoderm. Development 133, 3787–3796 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. 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). This paper suggests that the PrE arises from a population of GATA6-expressing cells that are spread throughout the ICM, rather than being formed on the basis of cell position. The authors also suggest that GRB2 is required for this process, demonstrating a role for receptor tyosine kinase signalling.

    Article  CAS  PubMed  Google Scholar 

  19. Arman, E., Haffner-Krausz, R., Chen, Y., Heath, J. K. & Lonai, P. 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, 5082–5087 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chiba, H. et al. Hepatocyte nuclear factor (HNF)-4α triggers formation of functional tight junctions and establishment of polarized epithelial morphology in F9 embryonal carcinoma cells. Exp. Cell Res. 286, 288–297 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Morrisey, E. E. et al. GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev. 12, 3579–3590 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Maurer, M. E. & Cooper, J. A. Endocytosis of megalin by visceral endoderm cells requires the Dab2 adaptor protein. J. Cell Sci. 118, 5345–5355 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Huang, C. L. et al. Disabled-2 is a negative regulator of integrin αIIbβ3-mediated fibrinogen adhesion and cell signaling. J. Biol. Chem. 279, 42279–42289 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Morrisey, E. E. et al. The gene encoding the mitogen-responsive phosphoprotein Dab2 is differentially regulated by GATA-6 and GATA-4 in the visceral endoderm. J. Biol. Chem. 275, 19949–19954 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Koutsourakis, M., Langeveld, A., Patient, R., Beddington, R. & Grosveld, F. The transcription factor GATA6 is essential for early extraembryonic development. Development 126, 723–732 (1999).

    CAS  PubMed  Google Scholar 

  26. Duncan, S. A., Nagy, A. & Chan, W. Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of Hnf-4−/− embryos. Development 124, 279–287 (1997).

    CAS  PubMed  Google Scholar 

  27. Fujikura, J. et al. Differentiation of embryonic stem cells is induced by GATA factors. Genes Dev. 16, 784–789 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang, D. H. et al. Disabled-2 is essential for endodermal cell positioning and structure formation during mouse embryogenesis. Dev. Biol. 251, 27–44 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Li, L. et al. Distinct GATA6- and laminin-dependent mechanisms regulate endodermal and ectodermal embryonic stem cell fates. Development 131, 5277–5286 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Guzman-Ayala, M., Ben Haim, N., Beck, S. & Constam, D. B. Nodal protein processing and fibroblast growth factor 4 synergize to maintain a trophoblast stem cell microenvironment. Proc. Natl Acad. Sci. USA 101, 15656–15660 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Goldin, S. N. & Papaioannou, V. E. Paracrine action of FGF4 during periimplantation development maintains trophectoderm and primitive endoderm. Genesis 36, 40–47 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Gotoh, N. et al. The docking protein FRS2α is an essential component of multiple fibroblast growth factor responses during early mouse development. Mol. Cell. Biol. 25, 4105–4116 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Thomas, P. & Beddington, R. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr. Biol. 6, 1487–1496 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Perea-Gomez, A. et al. OTX2 is required for visceral endoderm movement and for the restriction of posterior signals in the epiblast of the mouse embryo. Development 128, 753–765 (2001).

    CAS  PubMed  Google Scholar 

  35. Kimura, C. et al. Visceral endoderm mediates forebrain development by suppressing posteriorizing signals. Dev. Biol. 225, 304–321 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Rivera-Perez, J. A. & Magnuson, T. Primitive streak formation in mice is preceded by localized activation of Brachyury and Wnt3. Dev. Biol. 288, 363–371 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Yamamoto, M. et al. Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo. Nature 428, 387–392 (2004). This paper demonstrates the role of nodal signalling in movement of the DVE to the anterior side. Ectopic nodal expression can drive cell proliferation in the visceral endoderm, whereas nodal antagonists LEFTY1 and CER1 suppress cell proliferation on the future anterior side, providing a mechanism for visceral-endoderm migration.

    Article  CAS  PubMed  Google Scholar 

  38. Chazaud, C. & Rossant, J. Disruption of early proximodistal patterning and AVE formation in Apc mutants. Development 133, 3379–3387 (2006). A loss-of-function mutation in APC that leads to constitutive β-catenin activity shows that restriction of WNT signalling is important for early proximal–distal patterning. The epiblast assumes a proximal character, causing suppression of the DVE and promoting expression of posterior mesendodermal genes.

    Article  CAS  PubMed  Google Scholar 

  39. Takaoka, K. et al. The mouse embryo autonomously acquires anterior–posterior polarity at implantation. Dev. Cell 10, 451–459 (2006). In this paper, the authors provide evidence of asymmetry in gene expression in the PrE at the time of implantation. This is particularly interesting as it occurs independently of any influence of the uterine environment.

    Article  CAS  PubMed  Google Scholar 

  40. Rodriguez, T. A., Srinivas, S., Clements, M. P., Smith, J. C. & Beddington, R. S. Induction and migration of the anterior visceral endoderm is regulated by the extra-embryonic ectoderm. Development 132, 2513–2520 (2005). Embryological experiments show an inhibitory role for the ExE in the formation of the DVE. In embryos in which the ExE has been removed, markers of the AVE and DVE are expressed in a expanded domain. When ectopic ExE is added, AVE genes are repressed.

    Article  CAS  PubMed  Google Scholar 

  41. Richardson, L., Torres-Padilla, M. E. & Zernicka-Goetz, M. Regionalised signalling within the extraembryonic ectoderm regulates anterior visceral endoderm positioning in the mouse embryo. Mech. Dev. 123, 288–296 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Donnison, M. et al. Loss of the extraembryonic ectoderm in Elf5 mutants leads to defects in embryonic patterning. Development 132, 2299–2308 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Soares, M. L. et al. Functional studies of signaling pathways in peri-implantation development of the mouse embryo by RNAi. BMC Dev. Biol. 5, 28 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Su, L. K. et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–670 (1992).

    Article  CAS  PubMed  Google Scholar 

  45. Huelsken, J. et al. Requirement for β-catenin in anterior–posterior axis formation in mice. J. Cell Biol. 148, 567–578 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Liu, Y., Festing, M. H., Hester, M., Thompson, J. C. & Weinstein, M. Generation of novel conditional and hypomorphic alleles of the Smad2 gene. Genesis 40, 118–123 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Brennan, J. et al. Nodal signalling in the epiblast patterns the early mouse embryo. Nature 411, 965–969 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Waldrip, W. R., Bikoff, E. K., Hoodless, P. A., Wrana, J. L. & Robertson, E. J. Smad2 signaling in extraembryonic tissues determines anterior–posterior polarity of the early mouse embryo. Cell 92, 797–808 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Morkel, M. et al. β-Catenin regulates Cripto- and Wnt3-dependent gene expression programs in mouse axis and mesoderm formation. Development 130, 6283–6294 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Ding, J. et al. Cripto is required for correct orientation of the anterior–posterior axis in the mouse embryo. Nature 395, 702–707 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Yamamoto, M. et al. The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior–posterior patterning and node formation in the mouse. Genes Dev. 15, 1242–1256 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Winnier, G., Blessing, M., Labosky, P. A. & Hogan, B. L. Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev. 9, 2105–2116 (1995).

    Article  CAS  PubMed  Google Scholar 

  53. Mishina, Y., Suzuki, A., Ueno, N. & Behringer, R. R. Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes Dev. 9, 3027–3037 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Beppu, H. et al. BMP type II receptor is required for gastrulation and early development of mouse embryos. Dev. Biol. 221, 249–258 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Ben Haim, N. et al. The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4. Dev. Cell 11, 313–323 (2006). Using a nodal mutant that is resistant to cleavage by pro-protein convertases, the authors show that the immature nodal protein takes part in a regulatory loop that maintains the source of convertases, induces BMP4 and WNT3, and ultimately upregulates nodal expression.

    Article  CAS  PubMed  Google Scholar 

  56. Perea-Gomez, A. et al. Nodal antagonists in the anterior visceral endoderm prevent the formation of multiple primitive streaks. Dev. Cell 3, 745–756 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Iratni, R. et al. Inhibition of excess nodal signaling during mouse gastrulation by the transcriptional corepressor DRAP1. Science 298, 1996–1999 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Norris, D. P., Brennan, J., Bikoff, E. K. & Robertson, E. J. The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo. Development 129, 3455–3468 (2002).

    CAS  PubMed  Google Scholar 

  59. Kelly, O. G., Pinson, K. I. & Skarnes, W. C. The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development 131, 2803–2815 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Mohamed, O. A., Clarke, H. J. & Dufort, D. β-catenin signaling marks the prospective site of primitive streak formation in the mouse embryo. Dev. Dyn. 231, 416–424 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Zamir, E. A., Czirok, A., Cui, C., Little, C. D. & Rongish, B. J. Mesodermal cell displacements during avian gastrulation are due to both individual cell-autonomous and convective tissue movements. Proc. Natl Acad. Sci. USA 103, 19806–19811 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 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).

    CAS  PubMed  Google Scholar 

  63. Rivera-Perez, J. A., Mager, J. & Magnuson, T. Dynamic morphogenetic events characterize the mouse visceral endoderm. Dev. Biol. 261, 470–487 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Weber, R. J., Pedersen, R. A., Wianny, F., Evans, M. J. & Zernicka-Goetz, M. Polarity of the mouse embryo is anticipated before implantation. Development 126, 5591–5598 (1999).

    CAS  PubMed  Google Scholar 

  65. Srinivas, S., Rodriguez, T., Clements, M., Smith, J. C. & Beddington, R. S. P. Active cell migration drives the unilateral movements of the anterior visceral endoderm. Development 131, 1157–1164 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Rakeman, A. S. & Anderson, K. V. Axis specification and morphogenesis in the mouse embryo require Nap1, a regulator of WAVE-mediated actin branching. Development 133, 3075–3083 (2006). Some mouse embryos that lack NCKAP, a component of the WAVE actin regulatory complex, have a duplicated body axis. Others show a failure to close the neural tube and form a single heart tube. This paper reveals a connection between cytoskeletal organization and body-plan organization.

    Article  CAS  PubMed  Google Scholar 

  67. Kimura-Yoshida, C. et al. Canonical Wnt signaling and its antagonist regulate anterior–posterior axis polarization by guiding cell migration in mouse visceral endoderm. Dev. Cell 9, 639–650 (2005). This paper provides evidence that the DVE moves by active cell migration, controlled by WNT signalling. The authors show that WNT functions as a repulsive cue, whereas the WNT inhibitor DKK1 works as an attractant. They also show that DKK1 can substitute for OTX2 function in visceral-endoderm migration.

    Article  CAS  PubMed  Google Scholar 

  68. Kemp, C., Willems, E., Abdo, S., Lambiv, L. & Leyns, L. Expression of all Wnt genes and their secreted antagonists during mouse blastocyst and postimplantation development. Dev. Dyn. 233, 1064–1075 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Ciruna, B. & Rossant, J. FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev. Cell 1, 37–49 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Yamaguchi, T. P., Takada, S., Yoshikawa, Y., Wu, N. & McMahon, A. P. T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification. Genes Dev. 13, 3185–3190 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sun, X., Meyers, E. N., Lewandoski, M. & Martin, G. R. Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev. 13, 1834–1846 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chuai, M. et al. Cell movement during chick primitive streak formation. Dev. Biol. 296, 137–149 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lickert, H. et al. Dissecting Wnt/β-catenin signaling during gastrulation using RNA interference in mouse embryos. Development 132, 2599–2609 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Tanaka, S. S., Yamaguchi, Y. L., Tsoi, B., Lickert, H. & Tam, P. P. IFITM/Mil/Fragilis family proteins IFITM1 and IFITM3 play distinct roles in mouse primordial germ cell homing and repulsion. Dev. Cell 9, 745–756 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Saitou, M., Barton, S. C. & Surani, M. A. A molecular programme for the specification of germ cell fate in mice. Nature 418, 293–300 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Shimono, A. & Behringer, R. R. Angiomotin regulates visceral endoderm movements during mouse embryogenesis. Curr. Biol. 13, 613–617 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Hukriede, N. A. et al. Conserved requirement of Lim1 function for cell movements during gastrulation. Dev. Cell 4, 83–94 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Chen, X. & Gumbiner, B. M. Crosstalk between different adhesion molecules. Curr. Opin. Cell Biol. 18, 572–578 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Medina, A., Swain, R. K., Kuerner, K. M. & Steinbeisser, H. Xenopus paraxial protocadherin has signaling functions and is involved in tissue separation. EMBO J. 23, 3249–3258 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Unterseher, F. et al. Paraxial protocadherin coordinates cell polarity during convergent extension via Rho A and JNK. EMBO J. 23, 3259–3269 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Saga, Y. et al. MesP1 is expressed in the heart precursor cells and required for the formation of a single heart tube. Development 126, 3437–3447 (1999).

    CAS  PubMed  Google Scholar 

  82. Tam, P. P. et al. Sequential allocation and global pattern of movement of the definitive endoderm in the mouse embryo during gastrulation. Development 134, 251–260 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. Shawlot, W. & Behringer, R. R. Requirement for Lim1 in head-organizer function. Nature 374, 425–430 (1995).

    Article  CAS  PubMed  Google Scholar 

  84. Hart, A. H. et al. Mixl1 is required for axial mesendoderm morphogenesis and patterning in the murine embryo. Development 129, 3597–3608 (2002).

    CAS  PubMed  Google Scholar 

  85. Kimura, C., Shen, M. M., Takeda, N., Aizawa, S. & Matsuo, I. Complementary functions of Otx2 and Cripto in initial patterning of mouse epiblast. Dev. Biol. 235, 12–32 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Lewis, S. L. & Tam, P. P. Definitive endoderm of the mouse embryo: formation, cell fates, and morphogenetic function. Dev. Dyn. 235, 2315–2329 (2006).

    Article  PubMed  Google Scholar 

  87. Beck, S. et al. Extraembryonic proteases regulate Nodal signalling during gastrulation. Nature Cell Biol. 4, 981–985 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Hoodless, P. A. et al. FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse. Genes Dev. 15, 1257–1271 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Episkopou, V. et al. Induction of the mammalian node requires Arkadia function in the extraembryonic lineages. Nature 410, 825–830 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Meno, C. et al. Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol. Cell 4, 287–298 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Vincent, S. D., Dunn, N. R., Hayashi, S., Norris, D. P. & Robertson, E. J. Cell fate decisions within the mouse organizer are governed by graded Nodal signals. Genes Dev. 17, 1646–1662 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Dunn, N. R., Vincent, S. D., Oxburgh, L., Robertson, E. J. & Bikoff, E. K. Combinatorial activities of Smad2 and Smad3 regulate mesoderm formation and patterning in the mouse embryo. Development 131, 1717–1728 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Kubo, A. et al. Development of definitive endoderm from embryonic stem cells in culture. Development 131, 1651–1662 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. D'Amour, K. A. et al. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nature Biotech. 23, 1534–1541 (2005).

    Article  CAS  Google Scholar 

  95. Hart, A. H., Willson, T. A., Wong, M., Parker, K. & Robb, L. Transcriptional regulation of the homeobox gene Mixl1 by TGFβ and FoxH1. Biochem. Biophys. Res. Commun. 333, 1361–1369 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Cheng, S. K., Olale, F., Bennett, J. T., Brivanlou, A. H. & Schier, A. F. EGF–CFC proteins are essential coreceptors for the TGFβ signals Vg1 and GDF1. Genes Dev. 17, 31–36 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Andersson, O., Reissmann, E., Jornvall, H. & Ibanez, C. F. Synergistic interaction between Gdf1 and Nodal during anterior axis development. Dev. Biol. 293, 370–381 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Chen, C. et al. The Vg1-related protein Gdf3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryo. Development 133, 319–329 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Miura, S., Davis, S., Klingensmith, J. & Mishina, Y. BMP signaling in the epiblast is required for proper recruitment of the prospective paraxial mesoderm and development of the somites. Development 133, 3767–3775 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Kalantry, S. et al. The amnionless gene, essential for mouse gastrulation, encodes a visceral-endoderm-specific protein with an extracellular cysteine-rich domain. Nature Genet. 27, 412–416 (2001).

    Article  CAS  PubMed  Google Scholar 

  101. Yoshikawa, Y., Fujimori, T., McMahon, A. P. & Takada, S. Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse. Dev. Biol. 183, 234–242 (1997).

    Article  CAS  PubMed  Google Scholar 

  102. Marikawa, Y. Wnt/β-catenin signaling and body plan formation in mouse embryos. Semin. Cell Dev. Biol. 17, 175–184 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Eakin, G. S. & Behringer, R. R. Diversity of germ layer and axis formation among mammals. Semin. Cell Dev. Biol. 15, 619–629 (2004).

    Article  PubMed  Google Scholar 

  104. Behringer, R. R., Wakamiya, M., Tsang, T. E. & Tam, P. P. A flattened mouse embryo: leveling the playing field. Genesis 28, 23–30 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Idkowiak, J., Weisheit, G., Plitzner, J. & Viebahn, C. Hypoblast controls mesoderm generation and axial patterning in the gastrulating rabbit embryo. Dev. Genes Evol. 214, 591–605 (2004).

    Article  PubMed  Google Scholar 

  106. Bertocchini, F. & Stern, C. D. The hypoblast of the chick embryo positions the primitive streak by antagonizing nodal signaling. Dev. Cell 3, 735–744 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Bertocchini, F., Skromne, I., Wolpert, L. & Stern, C. D. Determination of embryonic polarity in a regulative system: evidence for endogenous inhibitors acting sequentially during primitive streak formation in the chick embryo. Development 131, 3381–3390 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Skromne, I. & Stern, C. D. Interactions between Wnt and Vg1 signalling pathways initiate primitive streak formation in the chick embryo. Development 128, 2915–2927 (2001).

    CAS  PubMed  Google Scholar 

  109. Albazerchi, A. & Stern, C. D. A role for the hypoblast (AVE) in the initiation of neural induction, independent of its ability to position the primitive streak. Dev. Biol. 301, 489–503 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Loh, Y. H. et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nature Genet. 38, 431–440 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Gu, G. et al. Global expression analysis of gene regulatory pathways during endocrine pancreatic development. Development 131, 165–179 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Shimono, A. & Behringer, R. R. Isolation of novel cDNAs by subtractions between the anterior mesendoderm of single mouse gastrula stage embryos. Dev. Biol. 209, 369–380 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Ilgren, E. B. The in vitro morphogenesis of the guinea pig egg cylinder. Anat. Embryol. 163, 351–365 (1981).

    Article  CAS  Google Scholar 

  114. Strumpf, D. et al. Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Development 132, 2093–2102 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Lawson, K. A., Meneses, J. J. & Pedersen, R. A. Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. Development 113, 891–911 (1991).

    CAS  PubMed  Google Scholar 

  116. Nicolas, J. F., Mathis, L., Bonnerot, C. & Saurin, W. Evidence in the mouse for self-renewing stem cells in the formation of a segmented longitudinal structure, the myotome. Development 122, 2933–2946 (1996).

    CAS  PubMed  Google Scholar 

  117. Tada, S. et al. Characterization of mesendoderm: a diverging point of the definitive endoderm and mesoderm in embryonic stem cell differentiation culture. Development 132, 4363–4374 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Robb, L. & Tam, P. P. Gastrula organiser and embryonic patterning in the mouse. Semin. Cell Dev. Biol. 15, 543–554 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Tam, P. P. & Beddington, R. S. Establishment and organization of germ layers in the gastrulating mouse embryo. Ciba Found. Symp. 165, 27–41 (1992).

    CAS  PubMed  Google Scholar 

  120. Kinder, S. J. et al. The orderly allocation of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo. Development 126, 4691–4701 (1999).

    CAS  PubMed  Google Scholar 

  121. Lickert, H. et al. Formation of multiple hearts in mice following deletion of β-catenin in the embryonic endoderm. Dev. Cell 3, 171–181 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Downs, K. M. & Davies, T. Staging of gastrulating mouse embryos by morphological landmarks in the dissecting microscope. Development 118, 1255–1266 (1993).

    CAS  PubMed  Google Scholar 

  123. Lu, C. C. & Robertson, E. J. Multiple roles for Nodal in the epiblast of the mouse embryo in the establishment of anterior–posterior patterning. Dev. Biol. 273, 149–159 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Conlon, F. L. et al. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 120, 1919–1928 (1994).

    CAS  PubMed  Google Scholar 

  125. Lowe, L. A., Yamada, S. & Kuehn, M. R. Genetic dissection of nodal function in patterning the mouse embryo. Development 128, 1831–1843 (2001).

    CAS  PubMed  Google Scholar 

  126. Chen, H. J. et al. The role of microtubule actin cross-linking factor 1 (MACF1) in the Wnt signaling pathway. Genes Dev. 20, 1933–1945 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Li, Y., Lu, W., He, X. & Bu, G. Modulation of LRP6-mediated Wnt signaling by molecular chaperone Mesd. FEBS Lett. 580, 5423–5428 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Shen for comments on the manuscript and H. Hamada for discussion. Our work is supported by the National Health and Medical Research Council (NHMRC) of Australia and Mr. J. Fairfax. P.P.L.T. is an NHMRC Senior Principal Research Fellow and D.A.F.L. is a Kimberly-Clark Research Fellow.

Author information

Authors and Affiliations

  1. Embryology Unit, Children's Medical Research Institute and Faculty of Medicine, University of Sydney, Westmead, 2145, NSW, Australia

    Patrick P. L. Tam & David A. F. Loebel

Authors
  1. Patrick P. L. Tam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David A. F. Loebel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick P. L. Tam.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Components of signalling pathways which operate during early mouse embryogenesis (PDF 67 kb)

Supplementary information S2 (table)

Gene activity associated with the formation of mesoderm and endoderm derivatives during gastrulation (PDF 90 kb)

Related links

Related links

FURTHER INFORMATION

CMRI Embryology Research Unit

Edinburgh Mouse Atlas Project

Gastrulation: From Cells to Embryo

The Mouse Genome Informatics Gene Expression Database

Glossary

Conceptus

All structures that develop from fertilization, including embryonic and extraembryonic structures.

Implantation

The attachment of the embryo to the uterine wall. In the mouse, this occurs about 4 days post coitum as the first step in establishing the maternal–fetal connection.

Blastocyst

The structure that the embryo adopts after the morula stage, 3.5–4.5 days post coitum, consisting of the trophoblast surrounding an inner cell mass and blastocoelic cavity.

Extraembryonic

Structures in the conceptus that do not contribute to the fetal tissues, including those derived from the trophoblast and primitive endoderm. These tissues support the growth of the embryo and are a source of signals for patterning.

Epiblast

A structure in the post-implantation embryo that develops from the inner cell mass, from which the ectoderm, mesoderm and definitive endoderm are derived.

Gastrulation

A stage of development in which the primary germ layers are formed (ectoderm, mesoderm and definitive endoderm), from which all the fetal tissues will develop.

Primitive streak

A structure that forms in the posterior region of the embryo and is the first visible sign of gastrulation. Epiblast cells ingress through the primitive streak and are allocated to the mesoderm or definitive endoderm.

Ingress

The process of cells entering the primitive streak.

Primary germ layers

The ectoderm, mesoderm and definitive endoderm cell layers that form at gastrulation, from which all fetal and some extraembryonic tissues develop.

Potency

The ability of a cell to differentiate into one or more cell types.

Morula

A stage of pre-implantation development in which the embryo is a ball containing 8–32 cells inside the zona pellucida. The outer cells will become the trophoblast and the inner cells will become the inner cell mass, from which the epiblast and subsequently the fetal tissues will form.

Fate mapping

An experimental approach by which the developmental fates of cells are traced from the tissue of origin to their destination and their contribution to specific types of tissues in the embryo is assessed.

Primitive endoderm

An extraembryonic cell layer that forms on the surface of the inner cell mass and faces the blastocoelic cavity. It gives rise to the visceral and parietal endoderm.

Blastocoele

A fluid-filled cavity within the blastocyst.

Epithelium

Cells that line the surface of a structure, characterized by tight cell junctions and polarized morphology.

Regionalization

The acquisition of localized morphological or molecular characteristics by cell populations within a tissue or an organ.

Homotypic interactions

Interactions between cells with similar cell-surface characteristics or molecular properties.

Epithelial-to-mesenchyme transition

A process during which cells lose their epithelial chracteristics, downregulate E-cadherin, gain a less regular appearance and become migratory.

Primordial germ cells

Diploid germline precursors that migrate through the gut endoderm layer and enter the gonad, where they differentiate into germ cells.

Paraxial mesoderm

The precursor of the somites, which give rise to the spine, muscle and dermis of the skin.

Prechordal plate

A mesoderm-derived structure that lies underneath the forebrain and anterior to the notochord.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tam, P., Loebel, D. Gene function in mouse embryogenesis: get set for gastrulation. Nat Rev Genet 8, 368–381 (2007). https://doi.org/10.1038/nrg2084

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2084

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing