A GATA4/WT1 cooperation regulates transcription of genes required for mammalian sex determination and differentiation.
BACKGROUND
In 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.


RESULTS
Although 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.


CONCLUSIONS
Our 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.
Miyamoto
Yoko
Y
Ontogeny-Reproduction Research Unit, Centre de Recherche du Centre Hospitalier Universitaire de Quebec (CRCHUQ), Quebec City, QC, G1V 4G2, Canada. yokomiyamo@hotmail.com
Taniguchi
Hiroaki
H
Hamel
Frédéric
F
Silversides
David W
DW
Viger
Robert S
RS
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D050991:GATA4 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D009095:Mullerian Ducts / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018000:Receptors, Peptide / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D019849:Sex Determination Processes; D012733:Sex Differentiation / Q000235:genetics*; D051876:Sex-Determining Region Y Protein / Q000235:genetics; D013045:Species Specificity; D013552:Swine / Q000235:genetics; D014158:Transcription, Genetic; D025721:WT1 Proteins / Q000378:metabolism*; D016335:Zinc Fingers
D050991:GATA4 Transcription Factor; D050505:Mutant Proteins; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D051876:Sex-Determining Region Y Protein; D025721:WT1 Proteins; C084621:anti-Mullerian hormone receptor