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Arkadia enhances nodal-related signalling to induce mesendoderm

Nature volume 410, pages 830–834 (2001)Cite this article

Abstract

Nodal-related members of the transforming growth factor (TGF)-β family regulate the induction of mesoderm, endoderm, and mesendoderm, a tissue specific to the Spemann organizer1,2,3,4,5,6,7. How these different tissues form in response to the same signalling molecules is not completely understood. It has been suggested that concentration-dependent effects, mediated by extracellular cofactors and antagonists, are responsible for the differences1,8,9,10. Here we show that the nuclear protein Arkadia specifically potentiates the mesendoderm-inducing activity of a subset of TGF-β family members. The combined activities of Arkadia and Xenopus nodal-related-1 are sufficient to induce mesendoderm and suppress mesoderm. Arkadia dorsalizes ventral tissues, resulting in the induction of organizer-specific gene expression. Blocking nodal signalling extracellularly inhibits these effects. Arkadia influences nodal activity when co-expressed and can function in cells adjacent to those producing the nodal signal. Our findings, together with the observation that Arkadia mutant mice lack a node and node-derived mesendoderm, identify Arkadia as an essential modulator of the nodal signalling cascade that leads to induction of Spemann's organizer.

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Figure 1: Arkadia expression and dorsalizing activity in ventral marginal zone explants (VMZs).
Figure 2: Arkadia enhanced the activities of dorsalizing TGF-β factors a–l, Morphology of explants after injection of inducer ± Arkadia RNA (250 pg).
Figure 3: Arkadia mimicked Xnr1 effects and required nodal signalling to function.
Figure 4: Arkadia does not alter signalling of TFG-β downstream effectors.
Figure 5: Arkadia functions in cells receiving the nodal signal and alters nodal signalling when co-expressed.

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References

  1. Schier, A. F. & Shen, M. M. Nodal signalling in vertebrate development. Nature 403, 385–389 (1999).

    Article  ADS  Google Scholar 

  2. Jones, C. M., Kuehn, M. R., Hogan, B. L. M., Smith, J. C. & Wright, C. V. E. Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation. Development 121, 3651–3662 (1995).

    CAS  PubMed  Google Scholar 

  3. 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 

  4. Feldman, B. et al. Zebrafish organizer development and germ-layer formation require nodal-related signals. Nature 395, 181–185 (1998).

    Article  ADS  CAS  Google Scholar 

  5. Rebagliati, M. R., Toyama, R., Fricke, C., Haffter, P. & Dawid, I. B. cyclops encodes a nodal-related factor involved in midline signaling. Proc. Natl Acad. Sci. USA 95, 9932–9937 (1998).

    Article  ADS  CAS  Google Scholar 

  6. Sampath, K. et al. Induction of the zebrafish ventral brain and floorplate requires cyclops/nodal signalling. Nature 395, 185–189 (1998).

    Article  ADS  CAS  Google Scholar 

  7. Zhou, X., Sasaki, H., Lowe, L., Hogan, B. L. M. & Kuehn, M. R. Nodal is a novel TGF-β-like gene expressed in the mouse node during gastrulation. Nature 361, 543–547 (1993).

    Article  ADS  CAS  Google Scholar 

  8. Piccolo, S. et al. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 397, 707–710 (1999).

    Article  ADS  CAS  Google Scholar 

  9. Gritsman, K. et al. The EGF-CFC protein one-eyed pinhead is essential for nodal signaling. Cell 97, 121–132 (1999).

    Article  CAS  Google Scholar 

  10. Bisgrove, B. W., Essner, J. J. & Yost, H. J. Regulation of midline development by antagonism of lefty and nodal signaling. Development 126, 3253–3262 (1999).

    CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  12. Graff, J. M., Thies, R. S., Song, J. J., Celese, A. J. & Melton, D. A. Studies with a Xenopus BMP receptor suggest that ventral mesoderm-inducing signals override dorsal signals in vivo. Cell 79, 169–179 (1994).

    Article  CAS  Google Scholar 

  13. Suzuki, A. et al. A truncated bone morphogenetic protein receptor affects dorsal-ventral patterning in the early Xenopus embryo. Proc. Natl Acad. Sci. USA 91, 10255–10259 (1994).

    Article  ADS  CAS  Google Scholar 

  14. Piccolo, S., Sasai, Y., Lu, B. & De Robertis, E. M. Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4. Cell 86, 589–598 (1996).

    Article  CAS  Google Scholar 

  15. Zimmerman, L. B., De Jesus-Escobar, J. M. & Harland, R. M. The Spemann organizer signal noggin binds and inactivates Bone Morphogenetic Protein 4. Cell 86, 599–606 (1996).

    Article  CAS  Google Scholar 

  16. Dale, L. & Jones, C. M. BMP signalling in early Xenopus development. BioEssays 21, 751–760 (1999).

    Article  CAS  Google Scholar 

  17. Smith, J. C., Price, B. M., Green, J. B., Weigel, D. & Herrmann, B. G. Expression of a Xenopus homolog of Brachyury (T) is an immediate-early response to mesoderm induction. Cell 67, 79–87 (1991).

    Article  CAS  Google Scholar 

  18. Jones, C. M., Dale, L., Hogan, B. L., Wright, C. V. & Smith, J. C. Bone morphogenetic protein-4 (BMP-4) acts during gastrula stages to cause ventralization of Xenopus embryos. Development 122, 1545–1554 (1996).

    CAS  PubMed  Google Scholar 

  19. Clements, D., Friday, R. V. & Woodland, H. R. Mode of action of VegT in mesoderm and endoderm formation. Development 126, 4903–4911 (1999).

    CAS  PubMed  Google Scholar 

  20. Agius, E., Oelgeschlager, M., Wessely, O., Kemp, C. & DeRobertis, E. M. Endodermal Nodal-related signals and mesoderm induction in Xenopus. Development 127, 1173–1183 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Armes, N. A. & Smith, J. C. The ALK-2 and ALK-4 activin receptors transduce distinct mesoderm-inducing signals during early Xenopus development but do not co-operate to establish thresholds. Development 124, 3797–3804 (1997).

    CAS  PubMed  Google Scholar 

  22. Sampath, K., Cheng, A. M. S., Frisch, A. & Wright, C. V. E. Functional differences among Xenopus nodal-related genes in left-right axis determination. Development 124, 3293–3302 (1997).

    CAS  PubMed  Google Scholar 

  23. Yasuo, H. & Lemaire, P. A two-step model for the fate determination of presumptive endodermal blastomeres in Xenopus embryos. Curr. Biol. 9, 869–879 (1999).

    Article  CAS  Google Scholar 

  24. Osada, S. I. & Wright, C. V. E. Xenopus nodal-related signaling is essential for mesendodermal patterning during early embryogenesis. Development 126, 3229–3240 (1999).

    CAS  PubMed  Google Scholar 

  25. Sun, B. I. et al. derriere: a TGF-beta family member required for posterior development in Xenopus. Development 126, 1467–1482 (1999).

    CAS  PubMed  Google Scholar 

  26. Zhang, J. et al. The role of maternal VegT in establishing the primary germ layers in Xenopus embryos. Cell 94, 515–524 (1998).

    Article  CAS  Google Scholar 

  27. Kofron, M. et al. Mesoderm induction in Xenopus is a zygotic event regulated by maternal VegT via TGFb growth factors. Development 126, 5759–5770 (1999).

    CAS  PubMed  Google Scholar 

  28. Massague, J. & Chen, Y.-G. Controlling TGF-b signaling. Genes Dev. 14, 627–644 (2000).

    CAS  PubMed  Google Scholar 

  29. 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).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank S. Piccolo for the Cer-S construct, and A. Ashworth, T. Enver, B. Feldman, A. Swain and members of the Jones laboratory for comments on the manuscript.

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Authors and Affiliations

  1. Section of Gene Function and Regulation, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK

    Christiane Niederländer & C. Michael Jones

  2. Mammalian Neurogenesis Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, DuCane Road, London, W12 0NN, UK

    James J. Walsh & Vasso Episkopou

Authors
  1. Christiane Niederländer
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  2. James J. Walsh
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  3. Vasso Episkopou
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  4. C. Michael Jones
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Corresponding author

Correspondence to C. Michael Jones.

Supplementary information

A.

Arkadia does not enhance the activity of activin protein in animal caps. Arkadia was expressed in the animal hemisphere by injection of RNA at the 2-cell stage. Animal caps were explanted at stage 8-9 and transferred into medium containing different concentrations of activin protein. No co-operation with the inductive effects of activin was observed. Results were confirmed by assaying the explants for molecular markers by RT-PCR (not shown).

B.

Arkadia expressing cells recruit non-expressing cells into secondary axes. Arkadia RNA was coinjected with nuclear beta gal RNA. Arkadia expressing cells (blue) populate all tissues in the secondary axes.

C.

Morphology of VegT expressing animal caps in the presence of Arkadia, and/or Cer-S. Arkadia has little effect on the morphology of VegT induced explants, but enhances endoderm formation while partially suppressing mesoderm formation (see molecular data in Figure 3).

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Niederländer, C., Walsh, J., Episkopou, V. et al. Arkadia enhances nodal-related signalling to induce mesendoderm. Nature 410, 830–834 (2001). https://doi.org/10.1038/35071103

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