WT1-Mediated Gene Regulation in Early Urogenital Ridge Development

Abstract

The Wilms tumor protein WT1 is involved in the development of several organs, including the gonads. WT1 mutations in humans lead to syndromes associated with impaired sexual development and Wt1 knockout mice show regression of gonad anlagen. As a transcription factor, WT1 fulfills its function by regulating a set of target genes. With respect to gonad development only few in vivo WT1 targets, e.g. steroidogenic factor 1 (SF1) have been identified so far. To get a comprehensive view of WT1 targets in the gonad, we compared gene expression in urogenital ridges of wild-type and Wt1^–/– embryos. We found almost 150 genes differentially expressed higher than factor three, using microarray analysis. To confirm these results we performed quantitative real-time RT-PCR for many genes and observed a high degree of concordance between microarray and real-time RT-PCR results. Employing in situ hybridization we found ‘WT1 activated genes’ to be expressed in gonads, mesonephroi and coelomic epithelium – those parts of the urogenital ridge with Wt1 expression. Interestingly, many of the differentially expressed genes are known to show sex-specific expression at later time-points. These results provide a basis for investigation of developmental pathways in the urogenital ridge downstream of WT1 and for identification of new candidate genes involved in early urogenital ridge development. For example we provide a first potential target of WT1 in the coelomic epithelium – Muc16, and a gene regulated by the WT1 target SF1 – Gata4.

WT1 controls antagonistic FGF and BMP-pSMAD pathways in early renal progenitors

“…Comparison of our data with previous microarray studies performed on gonadal ridges 21 or adult kidneys 22 from Wt1 mutant animals revealed little overlap ( Supplementary Fig. 2B), indicating that gene sets regulated by WT1 largely depend on tissue context.…”

Mesenchymal-to-Epithelial Transition Contributes to Endometrial Regeneration Following Natural and Artificial Decidualization

“…However, it is unknown whether the pancytokeratin and vimentin expressing ''stromal'' cells derive from a mesenchymal stem cell pool or whether dedifferentiationredifferentiation of mature stromal cells occurs. Due to the location of the co-localized cells at 24 h postovex at the stromal-myometrial border, we speculate that they originate from mesenchymal stem cells which are purported to reside in the same vicinity [25][26][27]. However, further investigation is needed to clearly determine the origin of these cells.…”

“…Several hypothesized mechanisms of regeneration have been proposed, and these include (1) re-epithelialization of the luminal epithelium by proliferation of residual glandular stumps [25,41,42]; (2) uterine mesenchymal and epithelial stem cells within the endometrium that give rise to lineage differentiating cells; and (3) endothelial, stromal, and epithelial cells that undergo cellular transdifferentiation to repopulate the endometrium [41]. More recent efforts indicate the existence of highly clonogenic epithelial and stromal cells obtained from human endometrium [43,44] as well as the presence of human endometrial side population cells that are characteristic of somatic stem cells [45].…”

Wilms’ tumour protein Wt1 stimulates transcription of the gene encoding vascular endothelial cadherin

“…To examine whether Wt1 is necessary for normal expression of VE-cadherin in vivo, transcript levels were measured by real-time RT-PCR in hearts, livers and urogenital ridges [18] of wild-type (Wt1 +/+ ), heterozygous (Wt1 +/− ) and Wt1-deficient (Wt1 −/− ) mouse embryos at E12.5 (Fig. 7).…”