Abstract
BackgroundIn mammals, sex determination is genetically controlled. The SRY gene, located on Y chromosome, functions as the dominant genetic switch for testis development. The SRY gene is specifically expressed in a subpopulation of somatic cells (pre-Sertoli cells) of the developing urogenital ridge for a brief period during gonadal differentiation. Despite this tight spatiotemporal expression pattern, the molecular mechanisms that regulate SRY transcription remain poorly understood. Sry expression has been shown to be markedly reduced in transgenic mice harboring a mutant GATA4 protein (a member of the GATA family of transcription factors) disrupted in its ability to interact with its transcriptional partner FOG2, suggesting that GATA4 is involved in SRY gene transcription.ResultsAlthough our results show that GATA4 directly targets the pig SRY promoter, we did not observe similar action on the mouse and human SRY promoters. In the mouse, Wilms' tumor 1 (WT1) is an important regulator of both Sry and Müllerian inhibiting substance (Amh/Mis) expression and in humans, WT1 mutations are associated with abnormalities of sex differentiation. GATA4 transcriptionally cooperated with WT1 on the mouse, pig, and human SRY promoters. Maximal GATA4/WT1 synergism was dependent on WT1 but not GATA4 binding to their consensus regulatory elements in the SRY promoter and required both the zinc finger and C-terminal regions of the GATA4 protein. Although both isoforms of WT1 synergized with GATA4, synergism was stronger with the +KTS rather than the -KTS isoform. WT1/GATA4 synergism was also observed on the AMH promoter. In contrast to SRY, WT1/GATA4 action on the mouse Amh promoter was specific for the -KTS isoform and required both WT1 and GATA4 binding.ConclusionOur data therefore provide new insights into the molecular mechanisms that contribute to the tissue-specific expression of the SRY and AMH genes in both normal development and certain syndromes of abnormal sex differentiation.
Highlights
IntroductionSex determination is genetically controlled. The SRY gene, located on Y chromosome, functions as the dominant genetic switch for testis development
In mammals, sex determination is genetically controlled
Numerous GATA binding sites are present in the different SRY promoters, they are not necessarily species conserved which is to be expected as SRY 5' flanking sequences are generally poorly conserved between mammals [52]
Summary
Sex determination is genetically controlled. The SRY gene, located on Y chromosome, functions as the dominant genetic switch for testis development. The SRY gene is expressed in a subpopulation of somatic cells (pre-Sertoli cells) of the developing urogenital ridge for a brief period during gonadal differentiation Despite this tight spatiotemporal expression pattern, the molecular mechanisms that regulate SRY transcription remain poorly understood. Sry mRNA is first detected by RT-PCR within the somatic cells of the indifferent genital ridges of male embryos at e10.5, with a peak of expression seen at e11.5 followed by a dramatic extinction of expression by e12.5 [8] These results have been confirmed by in situ hybridization [9] and at the protein level [10]. The genital ridge expression of SRY has been described for the pig, sheep, dog and goat, and collectively reveals the initiation of SRY transcription within the indifferent male genital ridge followed by a gradual trailing off of expression more similar to the human model of expression than to the mouse model [12,13,14,15,16]
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