1. ¹Department of Biochemistry, McGill University, Montreal, Quebec, Canada
2. ²Department of Pathology, University of Otago, Dunedin, New Zealand
3. ³Department of Pathology, Amgen, Inc., Thousand Oaks, CA, USA
4. ⁴Department of Pediatrics, Montreal Children's Hospital, McGill University, Montreal, Quebec, Canada
5. ⁵McGill Cancer Center, McGill University, Montreal, Quebec, Canada

Correspondence: M Eccles, Department of Pathology, Hercus Building Hanover Street, University of Otago, PO Box 913, Dunedin 9015, New Zealand. E-mail: meccles@otago.ac.nz

⁶Both these authors contributed equally to this work

Received 15 January 2003; Revised 19 May 2003; Accepted 15 July 2003.

Abstract

Metanephric kidney development requires an inductive interaction between the ureteric bud and progenitor mesenchyme, where the early expression of two genes, Wilms' tumour 1 (WT1) and paired box 2 (Pax2), establishes critical but unknown developmental pathways. Indeed, transgenic mice with deregulated overexpression of Pax2 exhibit structural kidney defects and impaired renal function, as do mice harboring targeted disruptions and/or spontaneous mutations of either the Pax2 or WT1 genes. WT1 and Pax2 are thought to regulate each other's expression during renal development. To better define the relationship between WT1 and Pax2, we generated mouse embryos containing heterozygous mutations in both genes. WT1^+/-/Pax2^1Neu/+ kidneys were 50% smaller than wild-type kidneys. They were characterized by severe attenuation of the renal medulla, and reduced development of calyces and the renal pelvis. Renal cortex development in compound heterozygotes culminated in fewer nephrons than in WT1^+/-, Pax2^1Neu/+ or wild-type mice. Only minor variations in the mesenchymal expression pattern of Pax2 protein, and the mRNA expression levels of Pax2 and WT1, were noted in mutant kidneys. We show that WT1 and Pax2 proteins interact in vitro and in vivo, demonstrating that WT1 and Pax2 can form a molecular complex. Our data suggest that WT1 is a modifier of the Pax2 mutant phenotype.