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Origin and role of distal visceral endoderm, a group of cells that determines anterior–posterior polarity of the mouse embryo

Nature Cell Biology volume 13, pages 743–752 (2011)Cite this article

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Abstract

Anterior–posterior polarity of the mouse embryo has been thought to be established when distal visceral endoderm (DVE) at embryonic day (E) 5.5 migrates toward the future anterior side to form anterior visceral endoderm (AVE). Lefty1, a marker of DVE and AVE, is asymmetrically expressed in implanting mouse embryos. We now show that Lefty1 is expressed first in a subset of epiblast progenitor cells and then in a subset of primitive endoderm progenitors. Genetic fate mapping indicated that the latter cells are destined to become DVE. In contrast to the accepted notion, however, AVE is not derived from DVE but is newly formed after E5.5 from Lefty1− visceral endoderm cells that move to the distal tip. Concomitant with DVE migration, all visceral endoderm cells in the embryonic region undergo global movement. In embryos subjected to genetic ablation of Lefty1-expressing DVE cells, AVE was formed de novo but the visceral endoderm including the newly formed AVE failed to migrate, indicating that DVE guides the migration of AVE by initiating the global movement of visceral endoderm cells. Future anterior–posterior polarity is thus already determined by Lefty1+ blastomeres in the implanting blastocyst.

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Figure 1: Two types of Lefty1+ cell in mouse embryos between E3.5 and E4.5.
Figure 2: Fates of Lefty1-expressing cells in the blastocyst.
Figure 3: Relation between DVE and descendants of Lefty1+ cells at E4.5.
Figure 4: DVE-derived cells do not overlap with AVE at E6.5.
Figure 5: Distinct origins of DVE and AVE.
Figure 6: Global movement of visceral endoderm cells.
Figure 7: Role of DVE in AVE formation.
Figure 8: Origin and role of DVE in anterior–posterior patterning.

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References

  1. Huynh, J. R. & St Johnston, D. The origin of asymmetry: early polarisation of the Drosophila germline cyst and oocyte. Curr. Biol. 14, R438–R449 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Beddington, R. S. & Robertson, E. J. Anterior patterning in mouse. Trends Genet. 14, 277–284 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Beddington, R. S. & Robertson, E. J. Axis development and early asymmetry in mammals. Cell 96, 195–209 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Rossant, J. & Tam, P. P. Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse. Development 136, 701–713 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Takaoka, K. et al. The mouse embryo autonomously acquires anterior–posterior polarity at implantation. Dev. Cell 10, 451–459 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Chazaud, C. & Rossant, J. Disruption of early proximodistal patterning and AVE formation in Apc mutants. Development 133, 3379–3387 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Torres-Padilla, M. E. et al. The anterior visceral endoderm of the mouse embryo is established from both preimplantation precursor cells and by de novo gene expression after implantation. Dev. Biol. 309, 97–112 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rossant, J., Chazaud, C. & Yamanaka, Y. Lineage allocation and asymmetries in the early mouse embryo. Phil. Trans. R. Soc. Lond. B Biol. Sci. 358, 1341–1348 (2003) (discussion 1349).

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. Plusa, B., Piliszek, A., Frankenberg, S., Artus, J. & Hadjantonakis, A. K. Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst. Development 135, 3081–3091 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Yamanaka, Y., Lanner, F. & Rossant, J. FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst. Development 137, 715–724 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Feil, R., Wagner, J., Metzger, D. & Chambon, P. Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochem. Biophys. Res. Commun. 237, 752–757 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Smith, L. J. Embryonic axis orientation in the mouse and its correlation with blastocyst relationships to the uterus. II. Relationships from 4 1/4 to 9 1/2 days. J. Embryol. Exp. Morphol. 89, 15–35 (1985).

    CAS  PubMed  Google Scholar 

  15. Gardner, R. L., Meredith, M. R. & Altman, D. G. Is the anterior–posterior axis of the fetus specified before implantation in the mouse? J. Exp. Zool. 264, 437–443 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Ferrer-Vaquer, A. et al. A sensitive and bright single-cell resolution live imaging reporter of Wnt/ss-catenin signaling in the mouse. BMC Dev. Biol. 10, 121 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yamamoto, M. et al. Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo. Nature 428, 387–392 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. 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 

  19. 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 

  20. Migeotte, I., Omelchenko, T., Hall, A. & Anderson, K. V. Rac1-dependent collective cell migration is required for specification of the anterior–posterior body axis of the mouse. PLoS Biol. 8, e1000442 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  21. 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 

  22. 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 

  23. Ivanova, A. et al. In vivo genetic ablation by Cre-mediated expression of diphtheria toxin fragment A. Genesis 43, 129–135 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Miura, S. & Mishina, Y. The DVE changes distal epiblast fate from definitive endoderm to neurectoderm by antagonizing nodal signaling. Dev. Dyn. 236, 1602–1610 (2007).

    Article  PubMed  Google Scholar 

  25. Chu, J. & Shen, M. M. Functional redundancy of EGF-CFC genes in epiblast and extraembryonic patterning during early mouse embryogenesis. Dev. Biol. 342, 63–73 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. 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 

  28. 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 

  29. 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 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. Yamamoto, M. et al. Antagonism between Smad1 and Smad2 signaling determines the site of distal visceral endoderm formation in the mouse embryo. J. Cell Biol. 184, 323–334 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mesnard, D., Filipe, M., Belo, J. A. & Zernicka-Goetz, M. The anterior–posterior axis emerges respecting the morphology of the mouse embryo that changes and aligns with the uterus before gastrulation. Curr. Biol. 14, 184–196 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Nagai, T. et al. A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications. Nat. Biotechnol. 20, 87–90 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Shaner, N. C. et al. Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nat. Biotechnol. 22, 1567–1572 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Copeland, N. G., Jenkins, N. A. & Court, D. L. Recombineering: a powerful new tool for mouse functional genomics. Nat. Rev. Genet. 2, 769–779 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Gong, S. et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917–925 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Saijoh, Y. et al. Distinct transcriptional regulatory mechanisms underlie left–right asymmetric expression of lefty-1 and lefty-2. Genes Dev. 13, 259–269 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank A. Fukumoto, H. Nishimura, K. Miyama, Y. Hamada, S. Ohishi, and K. Yamashita for technical assistance, A. Miyawaki for the mVenus complementary DNA and R. Tsien for tdTomato and Cherry cDNAs. This work was supported by a grant from CREST (Core Research for Evolutional Science and Technology) of the Japan Science and Technology Corporation as well as by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. K.T. was supported by a fellowship from the Japan Society for the Promotion of Science for Japanese Junior Scientists and Grant-in-Aid for Scientific Research on Innovative Areas.

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Authors and Affiliations

  1. Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, and CREST, Japan Science and Technology Corporation (JST), 1–3 Yamada-oka, Suita, Osaka 565-0871, Japan

    Katsuyoshi Takaoka, Masamichi Yamamoto & Hiroshi Hamada

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  1. Katsuyoshi Takaoka
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Contributions

Project planning was carried out mainly by K.T. and partly by M.Y. and H.H.; all experiments involving mouse embryos were carried out by K.T.; the manuscript was written by K.T. and H.H.

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Correspondence to Katsuyoshi Takaoka or Hiroshi Hamada.

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The authors declare no competing financial interests.

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Takaoka, K., Yamamoto, M. & Hamada, H. Origin and role of distal visceral endoderm, a group of cells that determines anterior–posterior polarity of the mouse embryo. Nat Cell Biol 13, 743–752 (2011). https://doi.org/10.1038/ncb2251

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