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:

DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis

Nature volume 390, pages 311–315 (1997)Cite this article

Abstract

Mutations in the DAX-1 gene are responsible for congenital X-linked adrenal hypoplasia, a disease that is associated with hypogonadotropic hypogonadism1,2. DAX-1 expression is tissue-specific and is finely regulated throughout development3,4,5, suggesting that it has a role in both adrenal and gonadal function. DAX-1 is an unusual member of the nuclear-receptor superfamily of transcription factors which contains no canonical zinc-finger or any other known DNA-binding motif1. Binding sites for DAX-1 are found in the promoters of the dax-1 and StAR (for steroidogenic acute regulatory protein) genes. Here we show that DAX-1 binds DNA and acts as a powerful transcriptional repressor of StAR gene expression, leading to a drastic decrease in steroid production. We provide in vitro and in vivo evidence that DAX-1 binds to DNA hairpin structures. Our results establish DAX-1 as the first member of the nuclear receptor superfamily with novel DNA-binding features and reveal that it has regulatory properties critical to the understanding of its physiological functions.

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: Preferential binding of DAX-1 to hairpin structures.
Figure 2: Presence of inverted repeats in the mouse dax-1 promoter.
Figure 3: Presence of hairpin H in the StAR promoter.
Figure 4: Formation of H1 in the mouse dax-1 promoter.
Figure 5: DAX-1 represses both dax-1 and StAR promoters.
Figure 6: Expression of DAX-1 in adrenal Y-1 cells blocks steroidogenesis.

Similar content being viewed by others

References

  1. Zanaria, E. et al. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372, 635–641 (1994).

    Article  Google Scholar 

  2. Muscatelli, F. et al. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypoganadotropic hypogonadism. Nature 372, 672–676 (1994).

    Article  Google Scholar 

  3. Swain, A. et al. Mouse Dax1 expression is consistent with a role in sex determination as well as in adrenal and hypothalamus function. Nature Genet. 12, 404–409 (1996).

    Article  CAS  Google Scholar 

  4. Ikeda, Y. et al. Steroidogenic factor 1 and Dax-1 colocalize in multiple cell lineages: Potential links in endocrine development. Mol. Endocrinol. 10, 1261–1272 (1996).

    Google Scholar 

  5. Tamai, K. T. et al. Hormonal and developmental regulation of DAX-1 expression in Sertoli cells. Mol. Endocrinol. 10, 1561–1569 (1996).

    CAS  PubMed  Google Scholar 

  6. Laudet, V., Stehelin, D. & Clevers, H. Ancestry and diversity of the HMG box superfamily. Nucleic Acids Res. 21, 2493–2501 (1993).

    Article  CAS  Google Scholar 

  7. Weir, H. M. et al. Structure of the HMG box motif in the B-domain of HMG-1. EMBO J. 12, 1311–1319 (1993).

    Article  Google Scholar 

  8. Bianchi, M. E., Beltrame, M. & Paonessa, G. Specific recognition of cruciform DNA by nuclear protein HMG1. Science 243, 1056–1059 (1989).

    Article  ADS  CAS  Google Scholar 

  9. Werner, M. H., Gronenborn, A. M. & Clore, M. G. Intercalation, DNA kinking, and the control of transcription. Science 271, 778–784 (1996).

    Article  ADS  CAS  Google Scholar 

  10. Stocco, D. M. & Clark, B. J. Regulation of the acute production of steroids in steroidogenic cells. Endocr. Rev. 17, 221–244 (1996).

    CAS  PubMed  Google Scholar 

  11. Clark, B. J., Wells, J., King, S. R. & Stocco, D. M. The purification, cloning and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. J. Biol. Chem. 269, 28314–28322 (1994).

    CAS  PubMed  Google Scholar 

  12. Lin, D. et al. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 267, 1828–1831 (1995).

    Article  Google Scholar 

  13. Palecek, E. Local supercoil-stabilized DNA structures. Crit. Rev. Biochem. Mol. Biol. 26, 151–226 (1991).

    Article  CAS  Google Scholar 

  14. Sugawara, T. et al. Structure of the human steroidogenic acute regulatory protein (StAR) gene: StAR stimualtes mitochondrial cholesterol 27-hydroxylase activity. Biochemsitry 34, 12506–12512 (1995).

    Article  Google Scholar 

  15. Lalli, E. et al. Atranscriptional silencing domain in DAX-1 whose mutation causes adrenal hypoplasia congenita. Mol. Endocrinol.(in the press).

  16. Schimmer, B. P. Adrenocortical Y1 cells. Meth. Enzymol. 58, 570–574 (1979).

    Google Scholar 

  17. Bose, H. S., Sugawara, T., Strauss, J. F. I & Miller, W. L. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N. Engl. J. Med. 335, 1870–1878 (1996).

    Article  Google Scholar 

  18. Caron, K. M. et al. Characterization of the promoter region of the mouse gene encoding the steroidogenic acute regulatory protein. Mol. Endocrinol. 11, 138–147 (1997).

    Article  Google Scholar 

  19. Sugawara, T., Holt, J. A., Kiriakidou, M. & Strauss, J. F. II Steroidogenic factor 1-dependent promoter activity of the human steroidogenic acute regulatory protein (StAR)gene. Biochemistry 35, 9052–9059 (1996).

    Article  CAS  Google Scholar 

  20. Sinclair, A. H. et al. Agene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346, 240–244 (1990).

    Article  ADS  CAS  Google Scholar 

  21. Bardoni, B. et al. Adosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nature Genet. 7, 497–501 (1994).

    Article  Google Scholar 

  22. Ito, M., Yu, R. & Jameson, J. L. DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenita. Mol. Cell. Biol. 17, 1476–1483 (1997).

    Article  Google Scholar 

  23. Clegg, C. H., Correll, L. A., Cadd, G. G. & McKnight, G. S. Inhibition of intracellular cAMP-dependent protein kinase using mutant genes of the regulatory type I subunit. J. Biol. Chem. 262, 13111–13119 (1987).

    Google Scholar 

  24. Foulkes, N. S., Borrelli, E. & Sassone-Corssi, P. CREM gene: Use of alternative DNA binding domains generates multiple antagonists of cAMP-induced transcription. Cell 64, 739–749 (1991).

    Article  CAS  Google Scholar 

  25. Laoide, B. M., Foulkes, N. S., Schlotter, F. & Sassone-Corssi, P. The functional versatility of CREM is determined by its modular structure. EMBO J. 12, 1179–1191 (1993).

    Article  Google Scholar 

Download references

Acknowledgements

We thank E. Remboutsika, M. Lamas, B. Bardoni, J. F. Strauss III, K. L. Parker, G. Camerino and E. Borrelli for help, discussions, and gifts of material, and E. Heitz, Y. Lutz, B. Boulay and S. Metz for technical assistance. E.Z. is an EEC postdoctoral fellow; E.L. was supported by a Telethon Italy Fellowship. This study was funded by grants from the NIH (to D.M.S.) and from CNRS, INSERM, Centre Hôspitalier Universitaire Régional, FRM, Rhône-Poulenc Rorer (Bioavenir) and ARC (P.S.-C.).

Author information

Author notes

  1. Emmanuel Zazopoulos, Enzo Lalli and Douglas M. Stocco: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS-INSERM-ULP BP 163, Illkirch, 67404, Strasbourg, France

    Paolo Sassone-Corsi

  2. Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, Lubbock, 79430, Texas, USA

    Douglas M. Stocco

Authors
  1. Emmanuel Zazopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Enzo Lalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Douglas M. Stocco
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paolo Sassone-Corsi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paolo Sassone-Corsi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zazopoulos, E., Lalli, E., Stocco, D. et al. DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis. Nature 390, 311–315 (1997). https://doi.org/10.1038/36899

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/36899

This article is cited by

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.

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