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Molecular and Cellular Biology, March 1999, p. 2289-2299, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Wilms' Tumor Suppressor Gene (wt1) Product Regulates Dax-1 Gene Expression during Gonadal Differentiation

Jungho Kim,1 Dirk Prawitt,2 Nabeel Bardeesy,1 Elena Torban,3 Caroline Vicaner,3 Paul Goodyer,3 Bernard Zabel,2 and Jerry Pelletier1,4,*

Department of Biochemistry,1 McGill Cancer Center,4 and Department of Pediatrics, Experimental Medicine,3 McGill University, Montreal, Quebec, Canada, and Department of Pediatrics, University of Mainz, D-55101 Mainz, Germany2

Received 9 July 1998/Returned for modification 26 August 1998/Accepted 6 November 1998

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.

* Corresponding author. Mailing address: Dept. of Biochemistry, McIntyre Medical Sciences Building, McGill University, Rm. 902, 3655 Drummond St., Montreal, Quebec, Canada H3G 1Y6. Phone: (514) 398-2323. Fax: (514) 398-7384. E-mail: Jerry{at}Med.Mcgill.ca.

Molecular and Cellular Biology, March 1999, p. 2289-2299, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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