Abstract
Patterning of the mouse embryo along the anteroposterior axis during body plan development requires migration of the distal visceral endoderm (DVE) towards the future anterior side by a mechanism that has remained unknown. Here we show that Nodal signalling and the regionalization of its antagonists are required for normal migration of the DVE. Whereas Nodal signalling provides the driving force for DVE migration by stimulating the proliferation of visceral endoderm cells, the antagonists Lefty1 and Cerl determine the direction of migration by asymmetrically inhibiting Nodal activity on the future anterior side.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Beddington, R. S. & Robertson, E. J. Anterior patterning in mouse. Trends Genet. 14, 277–284 (1998)
Beddington, R. S. & Robertson, E. J. Axis development and early asymmetry in mammals. Cell 96, 195–209 (1999)
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)
Meno, C. et al. Two closely-related left-right asymmetrically expressed genes, lefty-1 and lefty-2: their distinct expression domains, chromosomal linkage and direct neuralizing activity in Xenopus embryos. Genes Cells 2, 513–524 (1997)
Belo, J. A. et al. Cerberus-like is a secreted factor with neutralizing activity expressed in the anterior primitive endoderm of the mouse gastrula. Mech. Dev. 68, 45–57 (1997)
Belo, J. A. et al. Cerberus-like is a secreted BMP and nodal antagonist not essential for mouse development. Genesis 26, 265–270 (2000)
Kimura, C. et al. Visceral endoderm mediates forebrain development by suppressing posteriorizing signals. Dev. Biol. 225, 304–321 (2000)
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)
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)
Norris, D. P. & Robertson, E. J. Asymmetric and node-specific nodal expression patterns are controlled by two distinct cis-acting regulatory elements. Genes Dev. 13, 1575–1588 (1999)
Collignon, J., Varlet, I. & Robertson, E. J. Relationship between asymmetric nodal expression and the direction of embryonic turning. Nature 381, 155–158 (1996)
Belachew, S. et al. Cyclin-dependent kinase-2 controls oligodendrocyte progenitor cell cycle progression and is downregulated in adult oligodendrocyte progenitors. J. Neurosci. 22, 8553–8562 (2002)
Meno, C. et al. lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell 94, 287–297 (1998)
Simpson, E. H. et al. The mouse Cer1 (Cerberus related or homologue) gene is not required for anterior pattern formation. Dev. Biol. 213, 202–206 (1999)
Shawlot, W., Min Deng, J., Wakamiya, M. & Behringer, R. R. The cerberus-related gene, Cerr1, is not essential for mouse head formation. Genesis 26, 253–258 (2000)
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)
Sakuma, R. et al. Inhibition of Nodal signalling by Lefty mediated through interaction with common receptors and efficient diffusion. Genes Cells 7, 401–412 (2002)
Piccolo, S. et al. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 397, 707–710 (1999)
Huelsken, J. et al. Requirement for beta-catenin in anterior-posterior axis formation in mice. J. Cell Biol. 148, 567–578 (2000)
De Robertis, E. M., Larrain, J., Oelgeschlager, M. & Wessely, O. The establishment of Spemann's organizer and patterning of the vertebrate embryo. Nature Rev. Genet. 1, 171–181 (2000)
Schier, A. F. Axis formation and patterning in zebrafish. Curr. Opin. Genet. Dev. 11, 393–404 (2001)
Chen, Y. & Schier, A. F. Lefty proteins are long-range inhibitors of squint-mediated nodal signaling. Curr. Biol. 12, 2124–2128 (2002)
Cheng, A. M., Thisse, B., Thisse, C. & Wright, C. V. The lefty-related factor Xatv acts as a feedback inhibitor of nodal signaling in mesoderm induction and L-R axis development in Xenopus. Development 127, 1049–1061 (2000)
Meno, C. et al. Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol. Cell 4, 287–298 (1999)
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)
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)
Miller, J. R. et al. Establishment of the dorsal-ventral axis in Xenopus embryos coincides with the dorsal enrichment of dishevelled that is dependent on cortical rotation. J. Cell Biol. 146, 427–437 (1999)
Eyal-Giladi, H., Goldberg, M., Refael, H. & Avner, O. A direct approach to the study of the effect of gravity on axis formation in birds. Adv. Space Res. 14, 271–279 (1994)
Mizushima, S. & Nagata, S. pEF-BOS, a powerful mammalian expression vector. Nucleic Acids Res. 18, 5322 (1990)
Hayashi, Y., Koike, M., Matsutani, M. & Hoshino, T. Effects of fixation time and enzymatic digestion on immunohistochemical demonstration of bromodeoxyuridine in formalin-fixed, paraffin-embedded tissue. J. Histochem. Cytochem. 36, 511–514 (1988)
Acknowledgements
We thank E. Robertson for NodallacZ mutant mice; R. Beddington for the Hex probe; V. Gallo for expression vectors for Cdk and dominant negative Cdk; and N. Mine and Y. Ohnishi for help in improving the lipofection procedure. We also thank S. Srinivas for exchanging unpublished data. This work was supported by grants from the Ministry of Education, Science, Sports, and Culture of Japan (to C.M. and H.H.), a grant from CREST (Core Research for Evolutional Science and Technology) of the Japan Science and Technology Corporation (to H.H.), a grant from the NIH (to R.R.B.), and a grant from the Association pour la Recherche sur le Cancer and by funds from the INSERM, the CNRS and the Hopital Universitaire de Strasbourg (to S.-L.A.). M.Y. is a recipient of a fellowship from the Japan Society for the Promotion of Science for Japanese Junior Scientists.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Supplementary information
Supplementary Information
Includes supplementary figure legends and supplementary methods. (DOC 52 kb)
Supplementary Figure 1
Delayed migration of the DVE in FoxH1 mutant embryos. (PDF 213 kb)
Supplementary Figure 2
Nodal expression in FoxH1 mutant embryos. (PDF 856 kb)
Supplementary Figure 3
(see full legend) (PDF 1372 kb)
Supplementary Figure 4
Model for A-P determination by Nodal antagonists. (PDF 257 kb)
Supplementary Figure 5
Introduction of a lacZ-expression vector by lipofection. (PDF 173 kb)
Rights and permissions
About this article
Cite this article
Yamamoto, M., Saijoh, Y., Perea-Gomez, A. et al. Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo. Nature 428, 387–392 (2004). https://doi.org/10.1038/nature02418
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature02418
This article is cited by
-
Distinct pathways drive anterior hypoblast specification in the implanting human embryo
Nature Cell Biology (2024)
-
A 3D “sandwich” co-culture system with vascular niche supports mouse embryo development from E3.5 to E7.5 in vitro
Stem Cell Research & Therapy (2023)
-
Stem-cell-based embryo models for fundamental research and translation
Nature Materials (2021)
-
Vacuolar-type proton ATPase is required for maintenance of apicobasal polarity of embryonic visceral endoderm
Scientific Reports (2021)
-
Basement membrane remodelling regulates mouse embryogenesis
Nature (2020)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.