Abstract
The product of the Wilms' tumor gene, WT1, is essential for male sex determination and differentiation in mammals. In addition to causing Wilms' tumor, mutations in WT1 often cause two distinct but overlapping urogenital defects in men, Denys-Drash syndrome and Frasier syndrome. In this study we investigated the regulation of the sex determination gene SRY by WT1. Our results showed that WT1 up-regulates the SRY gene through the proximal early growth response gene-1-like DNA-binding sequences in the core promoter. Mutant WT1 proteins in Denys-Drash syndrome patients were unable to activate this promoter. These mutants did not act in a dominant negative manner, as expected over the wild-type WT1 in this promoter. We also found that WT1 could transactivate the endogenous SRY gene. These observations, together with the overlapping expression patterns of WT1 and SRY in human gonads, led us to propose that WT1 regulates SRY in the initial sex determination process in humans and activates a cascade of genes ultimately leading to the complete organogenesis of the testis.
Highlights
The Wilms’ tumor gene WT1 is involved in tumorigenesis in humans, and its mouse homolog, Wt1, has a distinct role in the development of several organs during embryogenesis [1, 2]
Our results showed that WT1 up-regulates the SRY gene through the proximal early growth response gene-1-like DNA-binding sequences in the core promoter
We found that WT1 could transactivate the endogenous SRY gene
Summary
The Wilms’ tumor gene WT1 is involved in tumorigenesis in humans, and its mouse homolog, Wt1, has a distinct role in the development of several organs during embryogenesis [1, 2]. WT1 is a zinc finger containing DNA-binding protein and acts as a transcriptional activator or repressor depending on the cellular or chromosomal context [8, 9]. It has four major isoforms, due to the insertion of three amino acids (KTS) between zinc fingers 3 and 4, and the insertion of an alternatively spliced 17-amino acid segment encoded by exon 5 in the middle of the protein (Fig. 1A) [10]. Our hypothesis is that because mutation of both genes causes sex reversal in humans and WT1 is expressed before SRY in the gonadal ridge, WT1 may regulate the expression of SRY. We provide clear evidence that WT1 activated the SRY gene and initiated a regulatory gene cascade in the male sex determination and differentiation pathway
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