Gata4 Is Required for Formation of the Genital Ridge in Mice

Abstract

In mammals, both testis and ovary arise from a sexually undifferentiated precursor, the genital ridge, which first appears during mid-gestation as a thickening of the coelomic epithelium on the ventromedial surface of the mesonephros. At least four genes ( Lhx9, Sf1, Wt1, and Emx2) have been demonstrated to be required for subsequent growth and maintenance of the genital ridge. However, no gene has been shown to be required for the initial thickening of the coelomic epithelium during genital ridge formation. We report that the transcription factor GATA4 is expressed in the coelomic epithelium of the genital ridge, progressing in an anterior-to-posterior (A-P) direction, immediately preceding an A-P wave of epithelial thickening. Mouse embryos conditionally deficient in Gata4 show no signs of gonadal initiation, as their coelomic epithelium remains a morphologically undifferentiated monolayer. The failure of genital ridge formation in Gata4-deficient embryos is corroborated by the absence of the early gonadal markers LHX9 and SF1. Our data indicate that GATA4 is required to initiate formation of the genital ridge in both XX and XY fetuses, prior to its previously reported role in testicular differentiation of the XY gonad.

Author Summary

During mammalian fetal development, the precursor of the testis or ovary first appears as a simple thickening, in a specific region, of the epithelial cell layer that lines the body cavity. The resulting structure is called the genital ridge, which then differentiates into either testis or ovary, depending on whether the sex chromosome constitution is XY or XX. A handful of genes, including Lhx9, Sf1, Wt1, and Emx2, are required to sustain the growth of the genital ridge. However, mice with mutations in any of these genes still undergo the initial step of epithelial thickening, suggesting that an additional step (or factor) is required to initiate genital ridge formation. We found that the evolutionarily conserved transcription factor GATA4 is expressed in the epithelium of the genital ridge before initial thickening. We produced a mouse with a Gata4 mutation in this tissue and demonstrated that the initial thickening does not take place; the mutant embryos fail to initiate gonad development. In support of this observation, the Gata4 mutant does not express the early gonadal markers LHX9 and SF1. These findings indicate that a genetically discrete, Gata4-dependent initiation step precedes the previously known processes that result in formation of testes and ovaries.