Coexpression of Wilms' tumor suppressor 1 (WT1) and androgen receptor (AR) in the genital tract of human male embryos and regulation of AR promoter activity by WT1.

Abstract

The Wilms' tumor suppressor 1 (WT1) is one of the key regulators of early male genital development. The androgen receptor (AR) is the major local factor responsible for the development of the male genitalia. As a subset of patients, with WT1 mutations and virilization defects, were found to present normal testosterone producing testes after birth, which suggests androgen resistance, we hypothesized that WT1 and AR might functionally interact during the development of the external genitalia. Coexpression of WT1 and AR was found in the mesenchyme surrounding the urogenital sinus, the mesonephros, and the Müllerian duct at 7 weeks p.c. and in the epididimys, vas deferens, and the gubernaculum testes from 13 to 27 weeks p.c. in human male embryos. A modification of AR expression by WT1 (WT1+/+, WT1+/-, and WT1+/- R394W) was seen in CV1, Hela, LNCaP, and T293 cells. WT1 was shown to increase or decrease AR expression depending on the cell line (1.6- to 3.7-fold). In this study, we consider LNCaP and T293 cells as the most physiological cell system, as both originate from the human urogenital tract. In these cell lines, a repressional effect of the mutant WT1+/- R394W (0.5-fold) on AR expression in comparison to the wild-type WT1+/- could be demonstrated. From our data, we conclude that a functional interaction of WT1 and AR might play a role during the development of the male external genitalia, but as the regulatory effects were moderate most likely in concert with other local cofactors.