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. 2007 Sep 18;104(38):14994-9.
doi: 10.1073/pnas.0701677104. Epub 2007 Sep 11.

Correct dosage of Fog2 and Gata4 transcription factors is critical for fetal testis development in mice

Gerrit J Bouma  1 , Linda L Washburn, Kenneth H Albrecht, Eva M Eicher
Affiliations

Correct dosage of Fog2 and Gata4 transcription factors is critical for fetal testis development in mice

Gerrit J Bouma et al. Proc Natl Acad Sci U S A. .

Abstract

Previous reports suggested that humans and mice differ in their sensitivity to the genetic dosage of transcription factors that play a role in early testicular development. This difference implies that testis determination might be somewhat different in these two species. We report that the Fog2 and Gata4 transcription factors are haploinsufficient for testis determination in mice. Whether gonadal sex reversal occurs depends on genetic background (i.e., modifier genes). For example, C57BL/6J (B6) XY mice develop testes if they are heterozygous for a mutant Fog2 (Fog2-) or Gata4 (Gata4(ki)) allele. However, if the B6 Y chromosome (Y(B6)) is replaced by the AKR Y chromosome (Y(AKR)), B6 Fog2-/+ XY(AKR) mice develop ovaries, and B6 Gata4(ki)/+ XY(AKR) mice develop ovaries and ovotestes (gonads containing both ovarian and testicular tissue). Furthermore, DBA/2J (D2) Fog2-/+ XY(AKR) mice and (B6 x D2)F1 hybrid Gata4(ki)/+ XY(AKR) mice develop testes. Sry is expressed in the mutant XY gonads, indicating that the lack of Sry expression is not the cause of ovarian tissue development in B6 Fog2-/+ or Gata4(ki)/+ XY(AKR) mice. However, up-regulation of Sox9 expression, which is critical for normal testicular development, does not occur in mutant XY gonads that develop as ovaries. We conclude that under certain genetic conditions, Sox9 up-regulation depends on the proper dosage of Fog2 and Gata4. We propose that in humans the FOG2 and/or GATA4 genes might be haploinsufficient for normal testis determination and thus could be the cause of some previously unassigned cases of XY gonadal sex reversal.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Embryonic day (E) 14.5–15 gonad–mesonephros complexes from normal (+/+) (A, D, G, and J), and heterozygous mutant Gata4ki (Gata4ki/+) (B, E, H, and K), and Fog2− (Fog2−/+) (C, F, I, and L) fetuses. (A) B6+/+ XX ovary. (B) B6 Gata4ki/+ XX ovary. (C) B6 Fog2−/+ XX ovary. (D) B6+/+ XYB6 testis. (E) B6 Gata4ki/+ XYB6 testis. (F) B6 Fog2−/+ XYB6 testis. (G) B6+/+ XYAKR testis. (H) B6 Gata4ki/+ XYAKR ovotestis. (I) B6 Fog2−/+ XYAKR ovary. (J) (B6 × D2)F1+/+ XYAKR testis. (K) (B6 × D2)F1 Gata4ki/+ XYAKR testis. (L) (B6 × D2)F1 Fog2−/+ XYAKR testis. In each case, the gonad (arrow in A) lies above the mesonephros. (E) Testis with attenuated cord growth. (H) Ovotestis. The arrowheads in H point to ovarian tissue.
Fig. 2.
Fig. 2.
Whole-mount immunohistochemical analysis of marker gene expression in E13.5 B6 Fog2−/+ XYAKR (top two rows) and B6 Gata4ki/+ XYAKR (bottom two rows) gonads, and B6 XX and B6 XYAKR control gonads. First and third rows illustrate expression of FGFR2 (green), AMH (red), and CD31 (PECAM; blue); the second and fourth rows illustrate expression of FOXL2 (green), AMH (red), and CD31 (PECAM; blue). The gonads in the first column (A, E, I, and M) are normal XX ovaries, and gonads in the second column (B, F, J, and N) are normal B6 XYAKR testes. Gonads in the third column are B6 Fog2−/+ XYAKR (C and G) and B6 Gata4ki/+ XYAKR (K and O) ovaries that appear similar to the control B6 XX ovaries (first column). Gonads in the fourth column are B6 Fog2−/+ XYAKR ovaries (D and H) and B6 Gata4ki/+ XYAKR ovotestes (L and P). In each image, the gonad lies above the mesonephros.
Fig. 3.
Fig. 3.
Relative Sry expression in E12 (A) and E14 (B) Fog2 and Gata4 B6 XYAKR homozygous normal gonads and heterozygous mutant gonads. At E14, only heterozygous mutant gonads classified as ovaries were used (i.e., no testicular cords observed). Expression levels are relative to 18S rRNA expression. The mean values represent the average values of a minimum of three cDNA samples (one cDNA sample represents both gonads from one fetus). *, Significant; P < 0.05 lower expression.
Fig. 4.
Fig. 4.
Expression pattern of fetal testicular-specific (A and B) and fetal ovarian-specific (C and D) genes in B6 Fog2 (A and C) and B6 Gata4 (B and D) homozygous normal and heterozygous mutant E14 gonads. Expression levels are relative to 18S rRNA expression. The mean values represent the average values of a minimum of three cDNA samples (one cDNA sample represents both gonads from one fetus). *, Significant (P < 0.05) higher (A and B) or lower (C and D) expression levels.
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References

    1. Achermann JC, Ito M, Hindmarsh PC, Jameson JL. Nat Genet. 1999;22:125–126. - PubMed
    1. Foster JW, Dominguez-Steglich MA, Guioli S, Kowk G, Weller PA, Stevanovic M, Weissenbach J, Mansour S, Young ID, Goodfellow PN, et al. Nature. 1994;372:525–530. - PubMed
    1. Wagner T, Wirth J, Meyer J, Zabel B, Held M, Zimmer J, Pasantes J, Bricarelli FD, Keutel J, Hustert E, et al. Cell. 1994;79:1111–1120. - PubMed
    1. Hastie ND. Hum Mol Genet. 1992;1:293–295. - PubMed
    1. Huang B, Wang S, Ning Y, Lamb AN, Bartley J. Am J Hum Genet. 1999;87:349–353. - PubMed

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