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J. Biol. Chem., Vol. 281, Issue 18, 12705-12712, May 5, 2006

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PAX2 Activates WNT4 Expression during Mammalian Kidney Development^*

Elena Torban, Alison Dziarmaga, Diana Iglesias, Lee Lee Chu, Tatiana Vassilieva, Melissa Little^¶, Michael Eccles^||, Maria Discenza^**, Jerry Pelletier^**, and Paul Goodyer, Recipient of a James McGill Research Chair¹

From the Departments of Experimental Medicine and Pediatrics and the Department of Human Genetics, McGill University, Montreal, Quebec, Canada, the ^¶Institute of Molecular Science, University of Queensland, Brisbane, Queensland, Australia, ^||Developmental Genetics Laboratory, Department of Pathology, University of Otago, Dunedin, New Zealand, and the ^**Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada

The transcription factor PAX2 is expressed during normal kidney development and is thought to influence outgrowth and branching of the ureteric bud. Mice with homozygous null Pax2 mutations have developmental defects of the midbrain-hindbrain region, optic nerve, and ear and are anephric. During nephrogenesis, PAX2 is also expressed by mesenchymal cells as they cluster and reorganize to form proximal elements of each nephron, but the function of PAX2 in these cells is unknown. In this study we hypothesized that PAX2 activates expression of WNT4, a secreted glycoprotein known to be critical for successful nephrogenesis. PAX2 protein was identified in distal portions of the "S-shaped" body, and the protein persists in the emerging proximal tubules of murine fetal kidney. PAX2 activated WNT4 promoter activity 5-fold in co-transfection assays with JTC12 cells derived from the proximal tubule. Inspection of the 5'-flanking sequence of the human WNT4 gene identified three novel PAX2 recognition motifs; each exhibited specific PAX2 protein binding in electromobility shift assays. Two motifs were contained within a completely duplicated 0.66-kb cassette. Transfection of JTC12 cells with a PAX2 expression vector was associated with a 7-fold increase in endogenous WNT4 mRNA. In contrast, Wnt4 mRNA was decreased by 60% in mesenchymal cell condensates of fetal kidney from mice with a heterozygous Pax2 mutation. We speculated that a key function of PAX2 is to activate WNT4 gene expression in metanephric mesenchymal cells as they differentiate to form elements of the renal tubules.

Received for publication, December 9, 2005

^* This work was supported by Operating Grants 62903 and 12954 from the Canadian Institutes of Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Montreal Children's Hospital Research Institute, 4060 Sainte Catherine St., West, Rm. 413, Montreal, H3Z 2Z3 Quebec, Canada. E-mail: Paul.Goodyer{at}muhc.mcgill.ca.

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