The Wilms' tumor suppressor gene (wt1) product regulates Dax-1 gene expression during gonadal differentiation.

Abstract

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.

• Authors: J Kim, D Prawitt, N Bardeesy, E Torban, C Vicaner, P Goodyer, B Zabel, J Pelletier
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 19 Issue 3 Pg. 2289-99 (Mar 1999) ISSN: 0270-7306 [Print] United States
• PMID: 10022915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DAX-1 Orphan Nuclear Receptor
• DNA-Binding Proteins
• NR0B1 protein, human
• Nr0b1 protein, mouse
• Receptors, Retinoic Acid
• Repressor Proteins
• Transcription Factors
• WT1 Proteins

Topics

• Animals
• Base Sequence
• COS Cells
• Cell Line, Transformed
• DAX-1 Orphan Nuclear Receptor
• DNA-Binding Proteins (genetics, physiology)
• Gene Expression Regulation, Developmental
• Genes, Wilms Tumor
• Gonads (embryology)
• Humans
• Mice
• Molecular Sequence Data
• Promoter Regions, Genetic
• Receptors, Retinoic Acid (genetics)
• Repressor Proteins
• Response Elements
• Transcription Factors (genetics, physiology)
• Transcriptional Activation
• WT1 Proteins