Correct Dosage of Fog2 and Gata4 Transcription Factors is Critical for Fetal Testis Development in Mice

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Sep 13

PMID 17848526

Citations 42

Authors

Gerrit J Bouma

Linda L Washburn

Kenneth H Albrecht

Eva M Eicher

Affiliations

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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.

Citing Articles

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Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function.

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