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.

  • Article
  • Published:

Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds

Nature Genetics volume 14, pages 62–68 (1996)Cite this article

Abstract

Heterozygous mutations in SOX9 lead to a human dwarfism syndrome, Campomelic dysplasia. Consistent with a role in sex determination, we find that Sox9 expression closely follows differentiation of Sertoli cells in the mouse testis, in experimental sex reversal when fetal ovaries are grafted to adult kidneys and in the chick where there is no evidence for a Sry gene. Our results imply that Sox9 plays an essential role in sex determination, possibly immediately downstream of Sry in mammals, and that it functions as a critical Sertoli cell differentiation factor, perhaps in all vertebrates.

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

Similar content being viewed by others

References

  1. Koopman, P., Gubbay, J., Vivian, N., Goodfellow, P.N. & Lovell-Badge, R. Male development of chromosomally female mice transgenic for Sry. Nature 351, 117–121 (1991).

    Article  CAS  PubMed  Google Scholar 

  2. Lovell-Badge, R. & Hacker, A. The molecular genetics of Sry and its role in mammalian sex determination. Phil. Trans. R. Soc. Lond. B., Bio. Sci. 305, 205–214 (1995).

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Gubbay, J. et al. A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature 346, 245–250 (1990).

    Article  CAS  PubMed  Google Scholar 

  5. Harley, V.R. et al. DNA binding activity of recombinant SRY from normal males and XY females. Science. 255, 453–456 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Pontiggia, A. et al. Sex reversing mutations affect the architecture of SRY-DNA complexes. EMBO J. 13, 6115–6124 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Koopman, P., Munsterberg, A., Capel, B., Vivian, N. & Lovell-Badge, R. Expression of a candidate sex-determining gene during mouse testis differentiation. Nature. 348, 450–452 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Jeske, Y.W., Bowles, J., Greenfield, A. & Koopman, P. Expression of a linear Sry transcript in the mouse genital ridge. Nature Genet. 10, 480–482 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Hacker, A., Capel, B., Goodfellow, P.N. & Lovell-Badge, R. Expression of Sry, the mouse sex determining gene. Development 121, 1603–1614 (1995).

    CAS  PubMed  Google Scholar 

  10. Palmer, S.J. & Burgoyne, P.S. In situ analysis of fetal, prepuberal and adult XX–XY chimaeric mouse testes: Sertoli cells are predominantly, but not exclusively, XY. Development 112, 265–268 (1991).

    CAS  PubMed  Google Scholar 

  11. McLaren, A. Germ cells and germ cell sex. Phil. Trans. R. Soc. Lond. B. 350, 229–233 (1995).

    Article  CAS  Google Scholar 

  12. Karl, J. & Capel, B. Three-dimensional structure of the developing mouse genital ridge. Phil. Trans. R. Soc. Lond. B. 350, 235–242 (1995).

    Article  CAS  Google Scholar 

  13. Buehr, M., Gu, S. & McLaren, A. Mesonephric contribution to testis differentiation in the fetal mouse. Development. 117, 273–281 (1993).

    CAS  PubMed  Google Scholar 

  14. Merchant Larios, H., Moreno Mendonza, N. & Buehr, M. The role of the mesonephros in cell differentiation and morphogenesis of the mouse fetal testis. Int. J. Dev. Biol. (1993).

  15. Jost, A., Vigier, B. & Prepin, J. Freemartins in cattle, the first steps of sexual organogenesis. J. Rep. Fertil. 29, 349–379 (1972).

    Article  CAS  Google Scholar 

  16. Behringer, R.R., The Mullerian inhibitor and mammalian sexual development. Phil. Trans. R. Soc. Lond. B. 350, 285–289 (1995).

    Article  CAS  Google Scholar 

  17. McElreavey, K., Vilain, E., Cotinot, C., Payen, E. & Fellous, M. Control of sex determination in animals. Eur. J. Bioch. 218, 769–783 (1993).

    Article  CAS  Google Scholar 

  18. Berkovitz, G.D., Fechner, P.Y., Marcantonio, S.M., Bland, G. & Stetten, G. The role of the sex-determinig region of the Y chromosome (SRY) in the etiology of 46, XX true hermaphroditism. Hum. Genet. 88, 411–416 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Meyers-Wallen, V.N. et al. Sry-negative XX sex reversal in the german shorthaired pointer dog. J. Hered. 86, 369–374 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Just, W. et al. Absence of Sry in species of the vole Ellobius. Nature Genet. 11, 117–118 (1996).

    Article  Google Scholar 

  21. Vigier, B., Watrin, F. Magre, S., Tran, D. & Josso, N. Purified bovine AMH induces a characteristic freemartin effect in fetal rat prospective ovaries exposed to it in vitro. Development 100, 43–55 (1987).

    CAS  PubMed  Google Scholar 

  22. Taketo, T. & Merchant-Larios, H. gonadal sex reversal of fetal mouse ovaries following transplantation into adult mice. In Prog. Dev. Biol., part A. 171–174 (1986).

  23. Graves, J.A.M. The evolution of mammalian sex chromosomes and the origin of sex determining genes. Phil. Trans. R. Soc. Lond. B. 350, 305–312 (1995).

    Article  CAS  Google Scholar 

  24. Collignon, J. et al. A comparison of the properties of Sox-3 with Sry and two related genes, Sox-1 and Sox-2. Development. 122, 509–520 (1996).

    CAS  PubMed  Google Scholar 

  25. Krishan, A., Haiden, G.J. & Shaffner, R.N. Mitotic chromosomes and the W sex chromosome of the great horned owl (Bubo v. virgianus). Chromosoma. 17, 258–263 (1965).

    Article  CAS  PubMed  Google Scholar 

  26. Ohno, S.K., W.D. & Kinosita, R. On the sex chromatin of Gallus domesticus. Exp. Cell Res. 19, 180–183 (1960).

    Article  CAS  PubMed  Google Scholar 

  27. Johnston, C.M., Barnett, M. & Sharpe, P.T. The molecular biology of temperature-dependent sex determination. Phil. Trans. R. Soc. Lond. 350, 297–304 (1995).

    CAS  Google Scholar 

  28. Foster, J.W. et al. Campomelic dysplasia and autosomal sex reversal caused by mutations in an SRY-related gene. Nature. 372, 525–530 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. Wagner, T. et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79, 1111–1120 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Wright, E. et al. The Sry-related gene Sox9 is expressed during chondrogenesis in mouse embryos. Nature Genet. 9, 15–20 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Kwok, C. et al. Mutations in Sox9, the gene responsible for Campomelic dysplasia and autosomal sex reversal. Am. Hum. Genet. 57, 1028–1036 (1995).

    CAS  Google Scholar 

  32. Foster, J.W. & Graves, J.A., An SRY-related sequence on the marsupial X chromosome: implications for the evolution of the mammalian testis determining gene. Proc. Natl. Acad. Sci. USA 91, 1927–1931 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Swain, A., Zanaria, E., Hacker, A., Lovell-Badge, R. & Camerino, G., 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  PubMed  Google Scholar 

  34. Shen, W.-H. et al. Nuclear receptor steroidigenic factor 1 regulates the Mullerian inhibiting substance gene: a link to the sex determination pathway. Cell 77, 651–661 (1994).

    Article  PubMed  Google Scholar 

  35. Coriat, A.M., Valleley, E., Ferguson, M.W. & Sharpe, P. Chromosomal and temperature-dependent sex determination: the search for a conserved mechanism. J. Exp. Zool. 270, 112–116 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Taketo-Hosotani, T., Merchant-Larios, H., Thau, R.B. & Koide, S.S. Testicular cell differentiation in fetal mouse ovaries following transplantation into adult male mice. J. Exp. Zool. 236, 229–237 (1985).

    Article  CAS  PubMed  Google Scholar 

  37. Houston, C.S. et al. The Campomelic syndrome: review, report of 17 cases, and follow-up on the currently 17-year-old boy first reported by Maroteaux et al. in 1971. Am. J. Med. Genet. 3–28 (1983).

  38. Elbrecht, A. & Smith, R.G. Aromatase enzyme activity and sex determination in chickens. Science. 225, 467–470 (1992).

    Article  Google Scholar 

  39. Travis, A., Amsterdam, A., Belanger, C. & Grosschedl, R. LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function. Genes Dev. 5, 880–894 (1991).

    Article  CAS  PubMed  Google Scholar 

  40. Whitfield, S., Lovell-Badge, R. & Goodfellow, P.N. Rapid sequence evolution of the the sex determining gene SRY. Nature 364, 713–715 (1993).

    Article  CAS  PubMed  Google Scholar 

  41. Sudbeck, P., Schmitz, M.L., Baeuerle, P.A. & Scherer, G. Sex reversal by loss of the C-terminal transactivation domain of human SOX9. Nature Genet. 13, 230–232 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Haqq, C.M. et al. Molecular basis of mammalian sexual determination: activation of Mullerian inhibiting substance gene expression by SRY. Science 266, 1494–1500 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Eusebe, D.C. et al. Cloning and expression of the chick anti-Mullerian hormone gene. J. Biol. Chem. 271, 4798–4804 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. Bitgood, M.J., Shen, L. & Mc-Mahon, A.P. Sertoli cell signaling by Desert Hedgehog regulates the male germline. Current Biol. 6, 298–304 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  46. Capel, B. et al. Deletion of Y chromosome sequences located outside the testis determining region can cause XY female sex reversal. Nature Genet. 5, 301–307 (1993).

    Article  CAS  PubMed  Google Scholar 

  47. Laval, S.H. et al. Y chromosome short arm-Sxr recombination in XSxr/Y males causes deletion of Rbm and XY female sex reversal. Proc. Natl. Acad. Sci. USA 92, 10403–10407 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Luo, X. et al. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77, 481–490 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Kreidberg, J.A. et al. Wt-1 is required for early kidney development. Cell 74, 679–691 (1993).

    Article  CAS  PubMed  Google Scholar 

  50. Hunt, P.A. & Eicher, E.M. Fertile male mice with three chromosomes: evidence that infertility in XYY male mice is an effect of two chromosomes. Chromosoma. 100, 293–299 (1991).

    Article  CAS  PubMed  Google Scholar 

  51. Lovell-Badge, R.H. & Robertson, E. XY female mice resulting from a heritable mutation in the murine primary testis determining gene. Tdy. Development 109, 635–646 (1990).

    CAS  PubMed  Google Scholar 

  52. Mahadevaiah, S.K., Lovell-Badge, R. & Burgoyne, P.S. Tdy-negative XY, XXY, XYY female mice: breeding data and synaptonemal complex analisys J. Reprod. Fert. 97, 151–160 (1993).

    Article  CAS  Google Scholar 

  53. Hamburger, V. & Hamilton, H.L. A series of normal stages in the development of the chick embryo. J. Morphol. 88, 49–92 (1951).

    Article  CAS  PubMed  Google Scholar 

  54. Clinton, M. A rapid protocol for sexing chick embryos (Gallus g.domesticus). Anim Genet. 25, 361–362 (1994).

    Article  CAS  PubMed  Google Scholar 

  55. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Bioch. 162, 156–159 (1987).

    Article  CAS  Google Scholar 

  56. Dresser, W.D., Hacker, A., Lovell-Badge, L. & Guerrier, D. The genes for a spliceosome protein (SAP62) and the anti-mullerian hormone (AMH) are contiguous. Hum. Mol. Genet. 4, 1613–1618 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Wilkinson, D. & Nieto, A.M. in Guide to techniques in mouse development. (P. M. de wassarman & M. L DePamphilis) 361–372 (Academic Press, New York, 1993).

    Book  Google Scholar 

  58. Harlow, E. & Lane, D. Antibodies: a laboratory manual. (Cold Spring Harbor Laboratory, Cold Spring Harbour, 1988).

    Google Scholar 

Download references

Author information

Author notes

  1. Adam Hacker

    Present address: Dept. of Developmental Neurobiology, United Medical and Dental School, Guy's Hospital, London, SE1 9RT, UK

Authors and Affiliations

  1. Division of Developmental Genetics, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

    Sara Morais da Silva, Adam Hacker, Amanda Swain & Robin Lovell-Badge

  2. Departmentof Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK

    Vince Harley & Peter Goodfellow

  3. The Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria, 3052, Australia

    Vince Harley

  4. SmithKline Beecham Pharmaceuticals, New Frontiers Sci. Park, Third Avenue, Harlow, Essex, CM19 5AW, UK

    Peter Goodfellow

Authors
  1. Sara Morais da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adam Hacker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vince Harley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Goodfellow
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Amanda Swain
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robin Lovell-Badge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robin Lovell-Badge.

Rights and permissions

Reprints and permissions

About this article

Cite this article

da Silva, S., Hacker, A., Harley, V. et al. Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds. Nat Genet 14, 62–68 (1996). https://doi.org/10.1038/ng0996-62

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0996-62

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