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.

  • Letter
  • Published:

Retinoic-acid signalling in node ectoderm and posterior neural plate directs left–right patterning of somitic mesoderm

Nature Cell Biology volume 8, pages 271–277 (2006)Cite this article

Abstract

Somitogenesis requires bilateral rhythmic segmentation of paraxial mesoderm along the antero-posterior axis1. The location of somite segmentation depends on opposing signalling gradients of retinoic acid (generated by retinaldehyde dehydrogenase-2; Raldh2) anteriorly and fibroblast growth factor (FGF; generated by Fgf8) posteriorly2,3. Retinoic-acid-deficient embryos exhibit somite left–right asymmetry4,5,6, but it remains unclear how retinoic acid mediates left–right patterning. Here, we demonstrate that retinoic-acid signalling is uniform across the left–right axis and occurs in node ectoderm but not node mesoderm. In Raldh2−/− mouse embryos, ectodermal Fgf8 expression encroaches anteriorly into node ectoderm and neural plate, but its expression in presomitic mesoderm is initially unchanged. The late stages of somitogenesis were rescued in Raldh2−/− mouse embryos when the maternal diet was supplemented with retinoic acid until only the 6-somite stage, demonstrating that retinoic acid is only needed during node stages. A retinoic-acid-reporter transgene marking the action of maternal retinoic acid in rescued Raldh2−/− embryos revealed that the targets of retinoic-acid signalling during somitogenesis are the node ectoderm and the posterior neural plate, not the presomitic mesoderm. Our findings suggest that antagonism of Fgf8 expression by retinoic acid occurs in the ectoderm and that failure of this mechanism generates excessive FGF8 signalling to adjacent mesoderm, resulting initially in smaller somites and then left–right asymmetry.

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: Retinoic-acid signalling is uniform across the left–right axis and present only in node ectoderm.
Figure 2: Bilateral somite-size defects precede left–right defects in the absence of retinoic-acid signalling.
Figure 3: Retinoic-acid signalling activity antagonizes Fgf8 expression only in ectoderm.
Figure 4: Retinoic-acid-signalling requirement for somitogenesis occurs only during the early somite stages.
Figure 5: The targets of retinoic-acid signalling for somitogenesis are the node ectoderm and the posterior neural plate.

Similar content being viewed by others

References

  1. Pourquié, O. The segmentation clock: converting embryonic time into spatial pattern. Science 301, 328–330 (2003).

    Article  Google Scholar 

  2. Del Corral, R.D. et al. Opposing FGF and retinoid pathways control ventral neural pattern, neuronal differentiation, and segmentation during body axis extension. Neuron 40, 65–79 (2003).

    Article  Google Scholar 

  3. Moreno, T.A. & Kintner, C. Regulation of segmental patterning by retinoic acid signaling during Xenopus somitogenesis. Dev. Cell 6, 205–218 (2004).

    Article  CAS  Google Scholar 

  4. Vermot, J. et al. Retinoic acid controls the bilateral symmetry of somite formation in the mouse embryo. Science 308, 563–566 (2005).

    Article  CAS  Google Scholar 

  5. Vermot, J. & Pourquié, O. Retinoic acid coordinates somitogenesis and left–right patterning in vertebrate embryos. Nature 435, 215–220 (2005).

    Article  CAS  Google Scholar 

  6. Kawakami, Y. et al. Retinoic acid signalling links left-right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo. Nature 435, 165–171 (2005).

    Article  CAS  Google Scholar 

  7. Dubrulle, J., McGrew, M.J. & Pourquié, O . FGF signaling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation. Cell 106, 219–232 (2001).

    Article  CAS  Google Scholar 

  8. Aulehla, A. & Herrmann, B.G. Segmentation in vertebrates: clock and gradient finally joined. Genes Dev. 18, 2060–2067 (2004).

    Article  CAS  Google Scholar 

  9. Molotkova, N., Molotkov, A., Sirbu, I.O. & Duester, G. Requirement of mesodermal retinoic acid generated by Raldh2 for posterior neural transformation. Mech. Dev. 122, 145–155 (2005).

    Article  CAS  Google Scholar 

  10. Niederreither, K. et al. Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse. Development 128, 1019–1031 (2001).

    CAS  PubMed  Google Scholar 

  11. Molotkov, A. et al. Stimulation of retinoic acid production and growth by ubiquitously-expressed alcohol dehydrogenase Adh3. Proc. Natl Acad. Sci. USA 99, 5337–5342 (2002).

    Article  CAS  Google Scholar 

  12. Niederreither, K., Subbarayan, V., Dollé, P. & Chambon, P. Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nature Genet. 21, 444–448 (1999).

    Article  CAS  Google Scholar 

  13. Mic, F.A., Haselbeck, R.J., Cuenca, A.E. & Duester, G. Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of Raldh2 null mutant mice. Development 129, 2271–2282 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Mic, F.A., Molotkov, A., Benbrook, D.M. & Duester, G. Retinoid activation of retinoic acid receptor but not retinoid X receptor is sufficient to rescue lethal defect in retinoic acid synthesis. Proc. Natl Acad. Sci. USA 100, 7135–7140 (2003).

    Article  CAS  Google Scholar 

  15. Rossant, J. et al. Expression of a retinoic acid response element-hsplacZ transgene defines specific domains of transcriptional activity during mouse embryogenesis. Genes Dev. 5, 1333–1344 (1991).

    Article  CAS  Google Scholar 

  16. Tanaka, Y., Okada, Y. & Hirokawa, N. FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left–right determination. Nature 435, 172–177 (2005).

    Article  CAS  Google Scholar 

  17. Morimoto, M., Takahashi, Y., Endo, M. & Saga, Y. The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity. Nature 435, 354–359 (2005).

    Article  CAS  Google Scholar 

  18. Bussen, M. et al. The T-box transcription factor Tbx18 maintains the separation of anterior and posterior somite compartments. Genes Dev. 18, 1209–1221 (2004).

    Article  CAS  Google Scholar 

  19. Sirbu, I.O., Gresh, L., Barra, J. & Duester, G. Shifting boundaries of retinoic acid activity control hindbrain segmental gene expression. Development 132, 2611–2622 (2005).

    Article  CAS  Google Scholar 

  20. MacLean, G. et al. Cloning of a novel retinoic-acid metabolizing cytochrome P450, Cyp26B1, and comparative expression analysis with Cyp26A1 during early murine development. Mech. Dev. 107, 195–201 (2001).

    Article  CAS  Google Scholar 

  21. Noy, N. Retinoid-binding proteins: mediators of retinoid action. Biochem. J. 348, 481–495 (2000).

    Article  CAS  Google Scholar 

  22. Ruberte, E., Dolle, P., Chambon, P. & Morriss–Kay, G. Retinoic acid receptors and cellular retinoid binding proteins. II. Their differential pattern of transcription during early morphogenesis in mouse embryos. Development 111, 45–60 (1991).

    CAS  PubMed  Google Scholar 

  23. Qiu, Y., Tsai, S.Y. & Tsai, M.–J. COUP–TF: An orphan member of the steroid–thyroid hormone receptor superfamily. Trends Endocrinol. Metab. 5, 234–239 (1994).

    Article  CAS  Google Scholar 

  24. Perantoni, A.O. et al. Inactivation of FGF8 in early mesoderm reveals an essential role in kidney development. Development 132, 3859–3871 (2005).

    Article  CAS  Google Scholar 

  25. Meyers, E.N. & Martin, G.R. Differences in left–right axis pathways in mouse and chick: functions of FGF8 and SHH. Science 285, 403–406 (1999).

    Article  CAS  Google Scholar 

  26. Molotkov, A., Molotkova, N. & Duester, G. Retinoic acid generated by Raldh2 in mesoderm is required for mouse dorsal endodermal pancreas development. Dev. Dyn. 232, 950–957 (2005).

    Article  CAS  Google Scholar 

  27. Mansouri, A. et al. Paired-related murine homeobox gene expressed in the developing sclerotome, kidney, and nervous system. Dev. Dyn. 210, 53–65 (1997).

    Article  CAS  Google Scholar 

  28. Kim, S.H. et al. The role of paraxial protocadherin in selective adhesion and cell movements of the mesoderm during Xenopus gastrulation. Development 125, 4681–4691 (1998).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the following for mouse cDNAs used to prepare in situ hybridization probes: G. Martin (Fgf8), Y. Saga (Mesp2), E. DeRobertis (Papc), A. Kispert (Tbx18), V. Giguere (Crabp2), M. Tsai (COUP–TFII) and A. Mansouri (Uncx4.1). We also thank J. Rossant for providing RARE–lacZ mice, and A. Molotkov, N. Molotkova and X. Zhao for helpful discussions. This work was funded by National Institutes of Health grant GM62848.

Author information

Authors and Affiliations

  1. OncoDevelopmental Biology Program, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, 92037, CA, USA

    Ioan Ovidiu Sirbu & Gregg Duester

Authors
  1. Ioan Ovidiu Sirbu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregg Duester
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gregg Duester.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sirbu, I., Duester, G. Retinoic-acid signalling in node ectoderm and posterior neural plate directs left–right patterning of somitic mesoderm. Nat Cell Biol 8, 271–277 (2006). https://doi.org/10.1038/ncb1374

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1374

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