6533b7d1fe1ef96bd125cc74
RESEARCH PRODUCT
The Wilms' tumor suppressor gene (wt1) product regulates Dax-1 gene expression during gonadal differentiation.
Jungho KimDirk PrawittJerry PelletierNabeel BardeesyCaroline VicanerBernard ZabelPaul GoodyerElena Torbansubject
Transcriptional Activationcongenital hereditary and neonatal diseases and abnormalitiesGenes Wilms TumorReceptors Retinoic AcidTATA boxMolecular Sequence DataMutagenesis (molecular biology technique)Biologyurologic and male genital diseasesResponse ElementsTransactivationMiceGene expressionAnimalsHumansGonadsPromoter Regions GeneticWT1 ProteinsMolecular BiologyGeneCell Growth and DevelopmentCell Line TransformedGonadal ridgeBase Sequenceurogenital systemDAX-1 Orphan Nuclear ReceptorfungiGene Expression Regulation DevelopmentalCell Biologyfemale genital diseases and pregnancy complicationsCell biologyDNA-Binding ProteinsRepressor ProteinsTestis determining factorNuclear receptorCOS CellsCancer researchTranscription Factorsdescription
Gonadal differentiation is dependent upon a molecular cascade responsible for ovarian or testicular development from the bipotential gonadal ridge. Genetic analysis has implicated a number of gene products essential for this process, which include Sry, WT1, SF-1, and DAX-1. We have sought to better define the role of WT1 in this process by identifying downstream targets of WT1 during normal gonadal development. We have noticed that in the developing murine gonadal ridge, wt1 expression precedes expression of Dax-1, a nuclear receptor gene. We document here that the spatial distribution profiles of both proteins in the developing gonad overlap. We also demonstrate that WT1 can activate the Dax-1 promoter. Footprinting analysis, transient transfections, promoter mutagenesis, and mobility shift assays suggest that WT1 regulates Dax-1 via GC-rich binding sites found upstream of the Dax-1 TATA box. We show that two WT1-interacting proteins, the product of a Denys-Drash syndrome allele of wt1 and prostate apoptosis response-4 protein, inhibit WT1-mediated transactivation of Dax-1. In addition, we demonstrate that WT1 can activate the endogenous Dax-1 promoter. Our results indicate that the WT1–DAX-1 pathway is an early event in the process of mammalian sex determination.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 1999-03-01 | Molecular and cellular biology |