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      Gata3 Acts Downstream of β-Catenin Signaling to Prevent Ectopic Metanephric Kidney Induction

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          Abstract

          Metanephric kidney induction critically depends on mesenchymal–epithelial interactions in the caudal region of the nephric (or Wolffian) duct. Central to this process, GDNF secreted from the metanephric mesenchyme induces ureter budding by activating the Ret receptor expressed in the nephric duct epithelium. A failure to regulate this pathway is believed to be responsible for a large proportion of the developmental anomalies affecting the urogenital system. Here, we show that the nephric duct-specific inactivation of the transcription factor gene Gata3 leads to massive ectopic ureter budding. This results in a spectrum of urogenital malformations including kidney adysplasia, duplex systems, and hydroureter, as well as vas deferens hyperplasia and uterine agenesis. The variability of developmental defects is reminiscent of the congenital anomalies of the kidney and urinary tract (CAKUT) observed in human. We show that Gata3 inactivation causes premature nephric duct cell differentiation and loss of Ret receptor gene expression. These changes ultimately affect nephric duct epithelium homeostasis, leading to ectopic budding of interspersed cells still expressing the Ret receptor. Importantly, the formation of these ectopic buds requires both GDNF/Ret and Fgf signaling activities. We further identify Gata3 as a central mediator of β-catenin function in the nephric duct and demonstrate that the β-catenin/Gata3 pathway prevents premature cell differentiation independently of its role in regulating Ret expression. Together, these results establish a genetic cascade in which Gata3 acts downstream of β-catenin, but upstream of Ret, to prevent ectopic ureter budding and premature cell differentiation in the nephric duct.

          Author Summary

          In humans, kidney development originates during embryonic development by the sprouting of an epithelial bud—called the ureteric bud—from a simple epithelial structure—the nephric duct. The ureteric bud quickly grows and branches in a treelike fashion to form the kidney collecting duct system, while the emerging ureteric tips induce nephron differentiation. One of the most important steps during kidney development is the positioning of a single ureteric bud along the nephric duct, since mutations of genes implicated in this process lead to severe urogenital malformations. In this study, we identified the Gata3 protein as a crucial regulator of ureteric bud positioning by using genetically modified mice. Deleting the Gata3 gene in the mouse resulted in the development of multiple kidneys emerging at improper positions. We show that this defect was caused by a hypersensitivity of nephric duct cells in their response to local growth signals. Interestingly, this phenomenon was partly triggered by premature differentiation of a subset of nephric duct cells. Furthermore, we report a genetic pathway in which Wnt/β-catenin signaling activates the Gata3 gene, which in turn positively regulates the Ret gene. In summary, we introduce a mouse model system that can be used to study human birth defects affecting the urogenital system.

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          Most cited references 58

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          Wnt/β-Catenin/Tcf Signaling Induces the Transcription of Axin2, a Negative Regulator of the Signaling Pathway

          Axin2/Conductin/Axil and its ortholog Axin are negative regulators of the Wnt signaling pathway, which promote the phosphorylation and degradation of β-catenin. While Axin is expressed ubiquitously, Axin2 mRNA was seen in a restricted pattern during mouse embryogenesis and organogenesis. Because many sites of Axin2 expression overlapped with those of several Wnt genes, we tested whether Axin2 was induced by Wnt signaling. Endogenous Axin2 mRNA and protein expression could be rapidly induced by activation of the Wnt pathway, and Axin2 reporter constructs, containing a 5.6-kb DNA fragment including the promoter and first intron, were also induced. This genomic region contains eight Tcf/LEF consensus binding sites, five of which are located within longer, highly conserved noncoding sequences. The mutation or deletion of these Tcf/LEF sites greatly diminished induction by β-catenin, and mutation of the Tcf/LEF site T2 abolished protein binding in an electrophoretic mobility shift assay. These results strongly suggest that Axin2 is a direct target of the Wnt pathway, mediated through Tcf/LEF factors. The 5.6-kb genomic sequence was sufficient to direct the tissue-specific expression of d2EGFP in transgenic embryos, consistent with a role for the Tcf/LEF sites and surrounding conserved sequences in the in vivo expression pattern of Axin2 . Our results suggest that Axin2 participates in a negative feedback loop, which could serve to limit the duration or intensity of a Wnt-initiated signal.
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            Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung.

            During mouse lung morphogenesis, the distal mesenchyme regulates the growth and branching of adjacent endoderm. We report here that fibroblast growth factor 10 (Fgf10) is expressed dynamically in the mesenchyme adjacent to the distal buds from the earliest stages of lung development. The temporal and spatial pattern of gene expression suggests that Fgf10 plays a role in directional outgrowth and possibly induction of epithelial buds, and that positive and negative regulators of Fgf10 are produced by the endoderm. In transgenic lungs overexpressing Shh in the endoderm, Fgf10 transcription is reduced, suggesting that high levels of SHH downregulate Fgf10. Addition of FGF10 to embryonic day 11.5 lung tissue (endoderm plus mesenchyme) in Matrigel or collagen gel culture elicits a cyst-like expansion of the endoderm after 24 hours. In Matrigel, but not collagen, this is followed by extensive budding after 48-60 hours. This response involves an increase in the rate of endodermal cell proliferation. The activity of FGF1, FGF7 and FGF10 was also tested directly on isolated endoderm in Matrigel culture. Under these conditions, FGF1 elicits immediate endodermal budding, while FGF7 and FGF10 initially induce expansion of the endoderm. However, within 24 hours, samples treated with FGF10 give rise to multiple buds, while FGF7-treated endoderm never progresses to bud formation, at all concentrations of factor tested. Although exogenous FGF1, FGF7 and FGF10 have overlapping activities in vitro, their in vivo expression patterns are quite distinct in relation to early branching events. We conclude that, during early lung development, localized sources of FGF10 in the mesoderm regulate endoderm proliferation and bud outgrowth.
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              Expression of a Delta homologue in prospective neurons in the chick.

              The product of the Delta gene, acting as ligand, and that of the Notch gene, acting as receptor, are key components in a lateral-inhibition signalling pathway that regulates the detailed patterning of many different tissues in Drosophila. During neurogenesis in particular, neural precursors, by expressing Delta, inhibit neighbouring Notch-expressing cells from becoming committed to a neural fate. Vertebrates are known to have several Notch genes, but their functions are unclear and their ligands hitherto unidentified. Here we identify and describe a chick Delta homologue, C-Delta-1. We show that C-Delta-1 is expressed in prospective neurons during neurogenesis, as new cells are being born and their fates decided. Our data from the chick, combined with parallel evidence from Xenopus, suggest that both the Delta/Notch signalling mechanism and its role in neurogenesis have been conserved in vertebrates.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                December 2008
                December 2008
                26 December 2008
                : 4
                : 12
                Affiliations
                [1 ]Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada
                [2 ]Department of Biochemistry, McGill University, Montreal, Quebec, Canada
                [3 ]Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria
                [4 ]Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States in America
                [5 ]Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States in America
                [6 ]Department of Genetics and Development, Columbia University Medical Center, New York, New York, United States in America
                Medical Research Council Human Genetics Unit, United Kingdom
                Author notes

                Conceived and designed the experiments: DG SKB MB. Performed the experiments: DG SKB. Analyzed the data: DG SKB MB. Contributed reagents/materials/analysis tools: CM XC FC TC. Wrote the paper: DG SKB MB. Generated Gata3 conditional mutant mice: AS. Critically reviewed the manuscript: CM XC FC TC.

                Article
                08-PLGE-RA-0628R2
                10.1371/journal.pgen.1000316
                2597718
                19112489
                Grote et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 12
                Categories
                Research Article
                Cell Biology/Cell Signaling
                Cell Biology/Gene Expression
                Developmental Biology/Cell Differentiation
                Developmental Biology/Developmental Molecular Mechanisms
                Developmental Biology/Organogenesis
                Nephrology/Hereditary, Genetic, and Development Nephrology

                Genetics

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