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      Yap- and Cdc42-Dependent Nephrogenesis and Morphogenesis during Mouse Kidney Development

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          Abstract

          Yap is a transcriptional co-activator that regulates cell proliferation and apoptosis downstream of the Hippo kinase pathway. We investigated Yap function during mouse kidney development using a conditional knockout strategy that specifically inactivated Yap within the nephrogenic lineage. We found that Yap is essential for nephron induction and morphogenesis, surprisingly, in a manner independent of regulation of cell proliferation and apoptosis. We used microarray analysis to identify a suite of novel Yap-dependent genes that function during nephron formation and have been implicated in morphogenesis. Previous in vitro studies have indicated that Yap can respond to mechanical stresses in cultured cells downstream of the small GTPases RhoA. We find that tissue-specific inactivation of the Rho GTPase Cdc42 causes a severe defect in nephrogenesis that strikingly phenocopies loss of Yap. Ablation of Cdc42 decreases nuclear localization of Yap, leading to a reduction of Yap-dependent gene expression. We propose that Yap responds to Cdc42-dependent signals in nephron progenitor cells to activate a genetic program required to shape the functioning nephron.

          Author Summary

          The mammalian kidney undergoes reiterative and stereotypical morphogenetic changes to create the elaborately convoluted adult nephron, the functional filtration unit of the kidney. How these sequential morphological events are controlled remains poorly understood. Here we show that the transcriptional activator Yap is essential in the developing murine kidney. Yap mutants have reduced nephrogenesis and defective morphogenesis. Yap function in nephrogenesis is independent of its previously described role in regulation of cell proliferation and apoptosis. Instead, Yap activity is needed for proper expression of a suite of genes that control cell signaling and cell structure. Remarkably, we find that ablation of Cdc42 phenocopies loss of Yap. We show that Cdc42 is essential for nuclear access of Yap, both in vivo and in tissue culture studies. Taken together, our work shows that Yap and Cdc42 are essential for the cell fate and morphogenesis decisions necessary to shape functioning nephrons, and suggests that Yap functions downstream of Cdc42 during kidney development.

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          Most cited references32

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          Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling.

          The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Hippo signaling: growth control and beyond.

            The Hippo pathway has emerged as a conserved signaling pathway that is essential for the proper regulation of organ growth in Drosophila and vertebrates. Although the mechanisms of signal transduction of the core kinases Hippo/Mst and Warts/Lats are relatively well understood, less is known about the upstream inputs of the pathway and about the downstream cellular and developmental outputs. Here, we review recently discovered mechanisms that contribute to the dynamic regulation of Hippo signaling during Drosophila and vertebrate development. We also discuss the expanding diversity of Hippo signaling functions during development, discoveries that shed light on a complex regulatory system and provide exciting new insights into the elusive mechanisms that regulate organ growth and regeneration.
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              Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development.

              Nephrons, the basic functional units of the kidney, are generated repetitively during kidney organogenesis from a mesenchymal progenitor population. Which cells within this pool give rise to nephrons and how multiple nephron lineages form during this protracted developmental process are unclear. We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent nephron progenitor population. Six2-expressing cells give rise to all cell types of the main body of the nephron during all stages of nephrogenesis. Pulse labeling of Six2-expressing nephron progenitors at the onset of kidney development suggests that the Six2-expressing population is maintained by self-renewal. Clonal analysis indicates that at least some Six2-expressing cells are multipotent, contributing to multiple domains of the nephron. Furthermore, Six2 functions cell autonomously to maintain a progenitor cell status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic nephron tubules, a mechanism dependent on a Wnt9b inductive signal. Taken together, our observations suggest that Six2 activity cell-autonomously regulates a multipotent nephron progenitor population.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                March 2013
                March 2013
                21 March 2013
                : 9
                : 3
                : e1003380
                Affiliations
                [1 ]Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
                [2 ]Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
                [3 ]Korea Advanced Institute of Science and Technology, Daejeon, Korea
                University of Michigan, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AR HM. Performed the experiments: AR RPS AG. Analyzed the data: AR RPS MB-L HM. Contributed reagents/materials/analysis tools: CC D-SL JW TP. Wrote the paper: AR HM.

                Article
                PGENETICS-D-12-02362
                10.1371/journal.pgen.1003380
                3605093
                23555292
                556cfc48-0ff1-43be-809b-0c3e253a4c60
                Copyright @ 2013

                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.

                History
                : 17 September 2012
                : 29 January 2013
                Page count
                Pages: 17
                Funding
                This work was supported by grants from the Canadian Institutes of Health Research (funding reference number 84468) and the Kidney Foundation of Canada to HM and by a postdoctoral fellowship from the FRM to AR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Developmental Biology
                Morphogenesis
                Pattern Formation
                Model Organisms
                Animal Models
                Mouse
                Molecular Cell Biology
                Signal Transduction
                Signaling Pathways
                Cell Growth
                Gene Expression

                Genetics
                Genetics

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