PMC:1858683 / 2449-5466 JSONTXT

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It is interesting to note that Wnt4 and Wnt11 have been shown to signal, at least in some cases, through noncanonical pathways [5-7], while there is evidence indicating that Wnt9b activates canonical Wnt signaling in the kidney [2].\nGenetic studies in Drosophila have identified the Pygopus (Pygo) gene as a critical component of canonical Wnt signaling [8-11]. Pygo and Lgs interact with β-catenin during the formation of the canonical transcriptional complex and are required for accumulation of β-catenin in the nucleus [12]. Lgs binds the central armadillo repeats of β-catenin, while Pygo interacts with Lgs, mediating activation of Wnt targets [9,13]. The N-terminal domain of Pygo is required for Wnt transcriptional activation, while the PHD motif is required for the association of Pygo with Lgs [9,13]. Additionally, a putative nuclear localization signal (NLS) was identified within the N-terminal domain of Pygo, suggesting a possible role of nuclear importation of β-catenin [8,11]. Analyses of multiple aspects of the pygopus mutant phenotype indicate that this gene is dedicated to, and required for, canonical Wnt signaling during Drosophila development [9].\nThe mammalian genome carries two, and only two, orthologs of Drosophila Pygo, Pygo1 and Pygo2 [8,9,14]. In this report, we generated targeted mutations of Pygo1 and Pygo2 to determine their functions, with a particular interest in the contributions of these genes to canonical Wnt signaling during kidney development. The resulting double-homozygous mutant embryos showed a context-dependent reduction in canonical Wnt signaling as measured by Wnt reporter transgene expression. Development remained, however, surprisingly normal, with survival to birth and few apparent defects in most organ systems. Our phenotypic analysis focused on the kidney, which showed altered branching morphogenesis of the ureteric bud, and expansion of the zone of condensed mesenchyme surrounding the ureteric bud, yet relatively normal nephron formation, as measured by histology, confocal analysis, in situ hybridization and microarray analysis. The obvious conclusion is that in mammals, unlike Drosophila, Pygopus-mediated canonical Wnt signaling is not absolutely necessary in most developing organ 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