title: PAX2 activates WNT4 expression during mammalian kidney development.
abstract: 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.
authors.affiliation: Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Elena
authors.initials: E
authors.lastname: Torban
authors.forename: Alison
authors.initials: A
authors.lastname: Dziarmaga
authors.forename: Diana
authors.initials: D
authors.lastname: Iglesias
authors.forename: Lee Lee
authors.initials: LL
authors.lastname: Chu
authors.forename: Tatiana
authors.initials: T
authors.lastname: Vassilieva
authors.forename: Melissa
authors.initials: M
authors.lastname: Little
authors.forename: Michael
authors.initials: M
authors.lastname: Eccles
authors.forename: Maria
authors.initials: M
authors.lastname: Discenza
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.forename: Paul
authors.initials: P
authors.lastname: Goodyer
mesh_terms: D000818:Animals; D001483:Base Sequence; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000737:chemistry; D006579:Heterozygote; D017403:In Situ Hybridization; D007668:Kidney / Q000196:embryology*; D007684:Kidney Tubules / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D051762:PAX2 Transcription Factor / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D051153:Wnt Proteins / Q000096:biosynthesis*; D060528:Wnt4 Protein
chemical_list: D006023:Glycoproteins; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; D011518:Proto-Oncogene Proteins; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse