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First published online June 8, 2005
doi: 10.1242/10.1242/dev.01890

Development 132, 3045-3054 (2005)
Published by The Company of Biologists 2005
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Gonadal sex reversal in mutant Dax1 XY mice: a failure to upregulate Sox9 in pre-Sertoli cells

Gerrit J. Bouma1,*, Kenneth H. Albrecht2, Linda L. Washburn1, Andrew K. Recknagel1, Gary A. Churchill1 and Eva M. Eicher1,*

1 The Jackson Laboratory, Bar Harbor, ME 04609, USA
2 Department of Medicine Genetics Program, and Department of Genetics and Genomics, Boston University School of Medicine, Boston, MA 02118, USA



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  		Fig. 1. Gross morphology of E14.5 gonad-mesonephros complexes. (A) B6 normal ovary. (B) B6 normal testis. (C) B6 Dax1-/+ ovary. (D) B6 Dax1-/Y ovary. (E) F1 Dax1+/Y testis. (F) F1 Dax1-/Y testis with abnormal cord development. In each image, the gonad is at the top and the mesonephros is at the bottom.

 


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  		Fig. 2. Confocal and whole-mount immunohistochemical analyses of marker gene expression and gonad morphology in B6 E12.5 and E13.5 gonad-mesonephros complexes. In each case, both marker gene expression and gonad morphology of Dax1-/Y ovaries are indistinguishable from normal Dax1+/+ ovaries. The top four rows illustrate the expression of GATA4, SF1, WT1 and SOX9 in E12.5 gonads (red staining). The bottom row illustrates AMH expression in E13.5 gonads (red staining). PECAM expression on the surface of germ cells and vascular endothelial cells is shown in each image (green staining). The left, middle and right columns are B6 Dax1+/+ ovaries, B6 Dax1-/Y ovaries and B6 Dax1+/Y testes, respectively. In each image the gonad is at the top and the mesonephros at the bottom.

 


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  		Fig. 3. Relative Sry expression in B6 Dax1-/Y and Dax1+/Y gonads as determined by real time RT-PCR analysis. y-axis indicates 18s RNA normalized Ct values. Black line illustrates the normalized threshold detection limit of the real time RT-PCR assay (Ct=37.5 - mean Ct 18s RNA). Values below this line indicate the gene is not expressed. An asterisk indicates a significant difference between B6 Dax1+/Y and B6 Dax1-/Y fetal gonads at P≤0.05.

 


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  		Fig. 4. Confocal and whole-mount immunohistochemical analyses of GATA4 (red) and PECAM1 (green) expression in B6 E13.5 gonad-mesonephros complexes: Dax1-/+ (A), Dax1-/YAKR (B), Dax1+/YAKR (C) and Dax1-/YAKR Tg2 (D). Dax1+/YAKR and Dax1-/YAKR Tg2 gonads have normal testis morphology and upregulated GATA4 expression in Sertoli cells compared with Dax1-/+ and Dax1-/YAKR gonads. PECAM expression is visible on the surface of germ cells and vascular endothelial cells. In each image, the gonad is at the top and the mesonephros at the bottom.

 


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  		Fig. 5. Genome scan of 123 backcross Dax1-/Y fetuses scored as 0 for male, 1 for hermaphrodite and 2 for female (A). Genome scan including only 17 male and 19 female backcross Dax1-/Y fetuses (B). (A,B) The y-axis provides the LOD score and the x-axis indicates the genomic location in genetic map units (cM) with chromosome numbers indicated. An allele interaction plot for Chrs 1 and 8 (C). The y-axis is scaled such that 0 represents male, 0.5 represents hermaphrodite and 1 represents female. The effect of Chr 8 on the tendency to produce females differs depending on the allelic stage of Chr 1, and Chr 1 has an effect on the sex ratio only when the Chr 8 locus is heterozygous. The lines in the plot indicate homozygosity B (B; open circles) and heterozygosity B/D (D; squares) for the Chr 1 locus.

 


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  		Fig. 6. Model for regulation of Sox9 expression in XY precursor somatic support cells. We hypothesize that upregulation of Sox9 is dependent on the correct expression levels of Sry, Dax1 and a gene (or genes) on distal Chr 4 referred to as Tda1 (testis-determining gene, autosomal 1). Perturbations in the expression level of any two of these three genes interferes with the upregulation of Sox9, and can result in the failure of the precursor somatic support cells to differentiate into Sertoli cells.

 




© The Company of Biologists Ltd 2005