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A transgenic insertion upstream of Sox9 is associated with dominant XX sex reversal in the mouse

Nature Genetics volume 26, pages 490–494 (2000)Cite this article

Abstract

In most mammals, male development is triggered by the transient expression of the Y-chromosome gene, Sry, which initiates a cascade of gene interactions ultimately leading to the formation of a testis from the indifferent fetal gonad1,2,3,4. Several genes5,6,7,8, in particular Sox9, have a crucial role in this pathway9,10,11,12,13,14. Despite this, the direct downstream targets of Sry and the nature of the pathway itself remain to be clearly established15,16. We report here a new dominant insertional mutation, Odsex (Ods), in which XX mice carrying a 150-kb deletion (approximately 1 Mb upstream of Sox9) develop as sterile XX males lacking Sry. During embryogenesis, wild-type XX fetal gonads downregulate Sox9 expression, whereas XY and XX Ods/+ fetal gonads upregulate and maintain its expression13,14. We propose that Ods has removed a long-range, gonad-specific regulatory element that mediates the repression of Sox9 expression in XX fetal gonads. This repression would normally be antagonized by Sry protein in XY embryos. Our data are consistent with Sox9 being a direct downstream target of Sry and provide genetic evidence to support a general repressor model of sex determination in mammals17,18.

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Figure 1: Phenotype of Ods-mutant mice.
Figure 2: Ods has created a deletion upstream of Sox9.
Figure 3: Mapping the Ods insertion site.
Figure 4: Histological analysis and Sox9 in situ hybridizations of fetal gonads.
Figure 5: A double-repressor model of mammalian sex determination.

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Acknowledgements

We thank G. Schuster for microinjections; L. Vien for animal husbandry and PCR assays; B. de Crombrugghe for the Sox9 in situ hybridization probe; H. Boettger-Tong for advice on several aspects of the work; and B. Capel and P. Koopman for discussion on the manuscript. Supported by grants from the National Institutes of Health (to C.E.B., R.R.B. and P.A.O.).

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Authors and Affiliations

  1. Department of Obstetrics & Gynecology, Baylor College of Medicine, Texas, Houston, USA

    Colin E. Bishop, Yanjun Qin, Alexander I. Agoulnik & Irina U. Agoulnik

  2. Department of Molecular Genetics, University of Texas M.D. Anderson Cancer Center, Texas, Houston, USA

    Deanne J. Whitworth & Richard R. Behringer

  3. Department of Pathology and Laboratory Medicine, University of Texas, Houston Health Science Center, Texas, Houston, USA

    Wilbur R. Harrison

  4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Texas, Houston, USA

    Irina U. Agoulnik, Wilbur R. Harrison & Paul A. Overbeek

  5. Department of Molecular and Human Genetics, Baylor College of Medicine, Texas, Houston, USA

    Colin E. Bishop & Paul A. Overbeek

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Correspondence to Colin E. Bishop.

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Bishop, C., Whitworth, D., Qin, Y. et al. A transgenic insertion upstream of Sox9 is associated with dominant XX sex reversal in the mouse. Nat Genet 26, 490–494 (2000). https://doi.org/10.1038/82652

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