%0 Journal Article
%T A GATA4/WT1 cooperation regulates transcription of genes required for mammalian sex determination and differentiation
%A Yoko Miyamoto
%A Hiroaki Taniguchi
%A Fr¨¦d¨¦ric Hamel
%A David W Silversides
%A Robert S Viger
%J BMC Molecular Biology
%D 2008
%I BioMed Central
%R 10.1186/1471-2199-9-44
%X 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 M¨¹llerian 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.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.In eutherian mammals, the gene responsible for triggering testis development, and hence male sex determination, is SRY (Sex Determining Region, Y chromosome) which encodes a putative transcription factor containing a high mobility group box DNA binding domain. SRY initiates the male pathway by triggering the differentiation of Sertoli cells in the genital ridge, the precursor of the developing gonad. During normal mammalian development, the tightly regulated spatiotemporal expression of SRY within the indifferent genital ridges is required for testis determination to proceed. Deregulation of this expression, either via insufficient SRY mRNA concentrations [1,2], delayed SRY expression [3], expression of different SRY isoforms [4], and/or the contribution of autosomal loci [5,6], can res
%U http://www.biomedcentral.com/1471-2199/9/44