Skip to main content
SpringerLink
Log in

The retinoid ligand 4-oxo-retinoic acid is a highly active modulator of positional specification

  • Letter
  • Published:

From Nature

View current issue Submit your manuscript

Abstract

RETINOIDS (vitamin A and its metabolites) are suspected of regulating diverse aspects of growth, differentiation, and patterning during embryogenesis1, but many questions remain about the identities and functions of the endogenous active retinoids involved. The pleiotropic effects of retinoids may be explained by the existence of complex signal transduction pathways involving diverse nuclear receptors of the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families, and at least two types of cellular retinoic acid binding proteins (CRABP-I and -II)2. The different RARs, RXRs, and CRABPs have different expression patterns during vertebrate embryogenesis2,3, suggesting that they each have particular functions. Another level at which fine tuning of retinoid action could occur is the metabolism of vitamin A to active metabolites, which may include all-trans-retinoic acid4–7, all-trans-3,4-didehydroretinoic acid8, 9-cis-retinoic acid9,10, and 14-hydroxy-4,14-retroretinol11. Formation of the metabolite all-trans-4-oxo-retinoie acid from retinoic acid was considered to be an inactivation pathway during growth and differentiation12–14. We report here that, in contrast, 4-oxo-retinoic acid is a highly active metabolite which can modulate positional specification in early embryos. We also show that this retinoid binds avidly to and activates RAR& beta;, and that it is available in early embryos. The different activities of 4-oxo-retinoic acid and retinoic acid in modulating positional specification on the one hand, and growth and differentiation on the other, interest us in the possibility that specific retinoid ligands regulate different physiological processes in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Maden, M. & Holder, H. Bioessays 14, 431–438 (1992).

    Article  CAS  Google Scholar 

  2. Leid, M., Kastner, P. & Chambon, P. Trends Biochem. Sci. 17, 427–433 (1992).

    Article  CAS  Google Scholar 

  3. Ellinger-Ziegelbauer, H. & Dreyer, C. Genes Dev. 5, 94–104 (1991).

    Article  CAS  Google Scholar 

  4. Tickle, C., Alberts, B., Wolpert, L. & Lee, J. Nature 296, 564–566 (1982).

    Article  ADS  CAS  Google Scholar 

  5. Thaller, C. & Eichele, G. Nature 327, 625–628 (1987).

    Article  ADS  CAS  Google Scholar 

  6. Durston, A. J. et al. Nature 340, 140–144 (1989).

    Article  ADS  CAS  Google Scholar 

  7. Hogan, B. L. M., Thaller, C. & Eichele, G. Nature 359, 237–241 (1992).

    Article  ADS  CAS  Google Scholar 

  8. Thaller, C. & Eichele, G. Nature 345, 815–819 (1990).

    Article  ADS  CAS  Google Scholar 

  9. Levin, A. A. et al. Nature 355, 359–361 (1992).

    Article  ADS  CAS  Google Scholar 

  10. Heyman, R. A. et al. Cell 68, 397–406 (1992).

    Article  CAS  Google Scholar 

  11. Buck, J. et al. Science 254, 1654–1656 (1991).

    Article  ADS  CAS  Google Scholar 

  12. Frolik, C. A. et al. Biochemistry 18, 2092–2097 (1979).

    Article  CAS  Google Scholar 

  13. Surekha Rao, M. S., John, J. & Cama, H. R. Int. J. Vitam. Nutr. Res. 42, 368–378 (1972).

    Google Scholar 

  14. Williams, J. B., Shoelds, C. O., Brettel, L. M. & Napoli, J. L. Analyt. Biochem. 160, 267–274 (1987).

    Article  CAS  Google Scholar 

  15. Sive, H. L., Draper, B. W., Harland, R. M. & Weintraub, H. Genes Dev. 4, 932–942 (1990).

    Article  CAS  Google Scholar 

  16. Ruiz i Altaba, A. & Jessell, T. Genes Dev. 5, 175–187 (1991).

    Article  CAS  Google Scholar 

  17. Wilkinson, D. G. et al. Nature 341, 405–409 (1989).

    Article  ADS  CAS  Google Scholar 

  18. Simeone, A. et al. Nature 346, 763–766 (1990).

    Article  ADS  CAS  Google Scholar 

  19. Dekker, E. J. et al. Mech. Dev. 40, 3–12 (1992).

    Article  Google Scholar 

  20. Eckhoff, C. & Nau, H. J. Lipid Res. 31, 1445–1454 (1990).

    CAS  PubMed  Google Scholar 

  21. Allenby, G. et al. Proc. natn. Acad. Sci. U.S.A. 90, 30–34 (1993).

    Article  ADS  CAS  Google Scholar 

  22. Nagpal, S. et al. Cell 70, 1007–1019 (1992).

    Article  CAS  Google Scholar 

  23. Folkers, G. E., van der Leede, B. M. & van der Saag, P. T. Molec. Endocr. 7, 616–627 (1993).

    CAS  PubMed  Google Scholar 

  24. Sani, B. P. in Retinoids (eds Livrea, M. A. & Packer, L.) 237–247 (Marcel Dekker, New York, 1993).

    Google Scholar 

  25. Frolik, C. A., Roller, P. P., Roberts, A. B. & Sporn, M. B. J. biol. Chem. 255, 8057–8062 (1980).

    CAS  PubMed  Google Scholar 

  26. Roberts, A. B., Lamb, L. C. & Sporn, M. B. Arch. Biochem. Biophys. 199, 374–383 (1980).

    Article  CAS  Google Scholar 

  27. Fiorella, P. D. & Napoli, J. L. J. biol. Chem. 266, 16572–16579 (1991).

    CAS  PubMed  Google Scholar 

  28. Nieuwkoop, P. D. et al. J. exp. Zool. 120, 1–108 (1952).

    Article  Google Scholar 

  29. Kao, K. R. & Elinson, R. P. Devl Biol. 127, 64–77 (1988).

    Article  CAS  Google Scholar 

  30. Palmer, F. B. St. C. Biochim. biophys. Acta 231, 134–144 (1971).

    Article  CAS  Google Scholar 

  31. Handyside, A. H., O'Neill, G. T., Jones, M. & Hooper, M. L. Roux's Arch. dev. Biol. 198, 48–55 (1989).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands

    W. W. M. Pijnappel, G. E. Folkers, C. E. van den Brink, E. J. Dekker, C. Edelenbosch, P. T. van der Saag & A. J. Durston

  2. TNO Institute of Ageing and Vascular Research (IVVO), PO Box 430, 2300 AK, Leiden, The Netherlands

    W. W. M. Pijnappel & H. F. J. Hendriks

Authors
  1. W. W. M. Pijnappel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. F. J. Hendriks
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G. E. Folkers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. E. van den Brink
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. J. Dekker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Edelenbosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P. T. van der Saag
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. J. Durston
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pijnappel, W., Hendriks, H., Folkers, G. et al. The retinoid ligand 4-oxo-retinoic acid is a highly active modulator of positional specification. Nature 366, 340–344 (1993). https://doi.org/10.1038/366340a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/366340a0

  • Springer Nature Limited

This article is cited by

Search

Navigation