Mus musculus
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ABSTRACT:
PROVIDER: PRJNA242749 | ENA |
REPOSITORIES: ENA
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Project description:p53 limits the self-renewing ability of a variety of stem cells. Here, contrary to its classical role in restraining cell proliferation, we demonstrate a divergent function of p53 in maintenance of self-renewal of the nephron progenitor population in the embryonic mouse kidney. p53-null nephron progenitor cells (NPC) exhibit progressive loss of the self-renewing progenitor niche in the cap mesenchyme, identified by Cited1 and Six2 expression, and loss of cap integrity. Nephron endowment is regulated by NPC availability and their differentiation to nephrons. Quantitatively, the Six2p53-/- cap has 30% fewer Six2GFP+ cells. While the apoptotic index is unchanged the proliferation index is significantly lower, in accordance with cell cycle analysis data showing less mutant Six2p53-/-;GFP+ cells in S and G2/M phases in comparison to Six2p53+/+;GFP+ cells. The mutant kidneys also show nephron deficit and decreased Fgf8 expression. To investigate the underlying changes in gene expression in the cap mesenchyme that contribute to the Six2p53-/- phenotype, we utilized RNA-Seq for transcriptome comparison. Top biological processes affected by p53 loss are development and morphogenesis, cell adhesion/migration, cell survival and metabolism. Cells from the mutant CM showed increased cellular ROS levels as well as deregulated expression of energy metabolism and mitochondrial genes suggesting metabolic dysfunction. Adhesion defects are visualized by decreased immunostaining of adhesion marker NCAM, and may possibly contribute to the differentiation defect as well. Altogether our data suggest a novel role for p53 in enabling self-renewal of the NPC and preservation of the progenitor niche, and thus regulating nephron endowment. mRNA profiles of wild-type (WT) and conditional p53 knockout (KO) of Six2+ mouse nephron progenitor cells (NPC) at embryonic day 15.5
2015-02-16 | E-GEOD-56253 | biostudies-arrayexpress
Project description:p53 limits the self-renewing ability of a variety of stem cells. Here, contrary to its classical role in restraining cell proliferation, we demonstrate a divergent function of p53 in maintenance of self-renewal of the nephron progenitor population in the embryonic mouse kidney. p53-null nephron progenitor cells (NPC) exhibit progressive loss of the self-renewing progenitor niche in the cap mesenchyme, identified by Cited1 and Six2 expression, and loss of cap integrity. Nephron endowment is regulated by NPC availability and their differentiation to nephrons. Quantitatively, the Six2p53-/- cap has 30% fewer Six2GFP+ cells. While the apoptotic index is unchanged the proliferation index is significantly lower, in accordance with cell cycle analysis data showing less mutant Six2p53-/-;GFP+ cells in S and G2/M phases in comparison to Six2p53+/+;GFP+ cells. The mutant kidneys also show nephron deficit and decreased Fgf8 expression. To investigate the underlying changes in gene expression in the cap mesenchyme that contribute to the Six2p53-/- phenotype, we utilized RNA-Seq for transcriptome comparison. Top biological processes affected by p53 loss are development and morphogenesis, cell adhesion/migration, cell survival and metabolism. Cells from the mutant CM showed increased cellular ROS levels as well as deregulated expression of energy metabolism and mitochondrial genes suggesting metabolic dysfunction. Adhesion defects are visualized by decreased immunostaining of adhesion marker NCAM, and may possibly contribute to the differentiation defect as well. Altogether our data suggest a novel role for p53 in enabling self-renewal of the NPC and preservation of the progenitor niche, and thus regulating nephron endowment.
2015-02-16 | GSE56253 | GEO
Project description:Regulation of the balance between progenitor self-renewal and differentiation is critical to development. In the mammalian kidney, reciprocal signaling between three lineages (stromal, mesenchymal and ureteric) ensures correct nephron progenitor self-renewal and differentiation. Loss of either the atypical cadherin Fat4 or its ligand Dachsous1 (Dchs1) results in expansion of the mesenchymal nephron progenitor pool, called the condensing mesenchyme (CM). This has been proposed to be due to misregulation of the Hippo kinase pathway transcriptional co-activator YAP. Here, we use tissue-specific deletions to prove that Fat4 acts non-autonomously in the renal stroma to control nephron progenitors. We show that loss of Yap from the CM in a Fat4-null background does not reduce the expanded CM, indicating Fat4 regulates the CM independent of YAP. Analysis of Six2-/-;Fat4-/- double mutants demonstrates that excess progenitors in Fat4 mutants are dependent on Six2, a critical regulator of nephron progenitor self-renewal. Electron microscopy reveals that cell organization is disrupted in Fat4 mutants. Gene expression analysis demonstrates that the expression of Notch and FGF pathway components are altered in Fat4 mutants. Finally, we show that Dchs1, and its paralog Dchs2 function in a partially redundant fashion to regulate the number of nephron progenitors. Our data supports a model in which FAT4 in the stroma binds to DCHS1/2 in the CM to restrict progenitor self-renewal. A total of 3 Fat4-/- mutant embryos and 3 wildtype (Fat4+/+) control embryos were examined. Two kidneys from each embryo was used thereby yielding a total of 6 Fat4-/- mutant kidneys and 6 Fat4+/+ wildype kidneys. All kidneys examined were at E13.5.
2015-08-01 | E-GEOD-70452 | biostudies-arrayexpress
Project description:DNA methylation regulates nephron progenitor cell renewal and differentiation
| PRJNA368816 | ENA
Project description:Regulation of the balance between progenitor self-renewal and differentiation is critical to development. In the mammalian kidney, reciprocal signaling between three lineages (stromal, mesenchymal and ureteric) ensures correct nephron progenitor self-renewal and differentiation. Loss of either the atypical cadherin Fat4 or its ligand Dachsous1 (Dchs1) results in expansion of the mesenchymal nephron progenitor pool, called the condensing mesenchyme (CM). This has been proposed to be due to misregulation of the Hippo kinase pathway transcriptional co-activator YAP. Here, we use tissue-specific deletions to prove that Fat4 acts non-autonomously in the renal stroma to control nephron progenitors. We show that loss of Yap from the CM in a Fat4-null background does not reduce the expanded CM, indicating Fat4 regulates the CM independent of YAP. Analysis of Six2-/-;Fat4-/- double mutants demonstrates that excess progenitors in Fat4 mutants are dependent on Six2, a critical regulator of nephron progenitor self-renewal. Electron microscopy reveals that cell organization is disrupted in Fat4 mutants. Gene expression analysis demonstrates that the expression of Notch and FGF pathway components are altered in Fat4 mutants. Finally, we show that Dchs1, and its paralog Dchs2 function in a partially redundant fashion to regulate the number of nephron progenitors. Our data supports a model in which FAT4 in the stroma binds to DCHS1/2 in the CM to restrict progenitor self-renewal.
2015-08-01 | GSE70452 | GEO
Project description:The regulation of final nephron number in the kidney is poorly understood. However, cessation of nephron formation occurs when the self-renewing nephron progenitor population commits to differentiation. Transcription factors within this progenitor population, such as SIX2, are assumed to control expression of genes promoting self-renewal such that homozygous Six2 deletion results in premature commitment and an early halt to kidney development. In contrast, Six2 heterozygotes were assumed to be unaffected. Using quantitative morphometry, we demonstrate here a paradoxical 18% increase in ureteric branching and final nephron number in Six2 heterozygotes, despite evidence for reduced levels of SIX2 protein and transcript. This is accompanied by a clear shift in nephron progenitor identity with a distinct subset of progenitor genes, including Cited1 and Meox1, downregulated, while others were unaffected. The net result was an increase in nephron progenitor proliferation, as assessed by elevated EDU labelling, an increase in MYC protein and transcriptional upregulation of MYC target genes. Reducing proliferation by introducing Six2 heterozygosity onto the Fgf20-/- background resulted in premature differentiation of the progenitor population. Overall, this data demonstrates a unique dose response of the nephron progenitors to the level of SIX2 protein in which the role of SIX2 in progenitor proliferation versus self-renewal is separable.
2017-12-31 | GSE103219 | GEO
Project description:Kidney development depends on a balance of nephron progenitor self-renewal and commitment. Here we examine how cells shift from a motile progenitor state to a static committed state during nephrogenesis. Cells that express Wnt4, an early marker of commitment, give rise to both the nephron lineage and a migrating sub-population that may re-enter the progenitor pool. Single cell transcriptional profiling reveals Wnt4-lineage cells across a range of transcriptional states, including cells that return to an uninduced progenitor state.
2019-01-31 | GSE118486 | GEO
Project description:Gene expression microarray analysis was performed on E15.5 p53+/+ and p53-/- litter-matched kidneys. We have previously shown that p53 is expressed in both UB and MM lineages in the kidney, and that p53-null embryos on C57B6L background exhibit a range of congenital abnormalities of the kidney and urinary tract such as duplicated ureters, reduced nephron numbers, and compromised nephron progenitor renewal and differentiation. Here our goal was to reveal the p53 transcriptome in mouse embryonic kidneys at E15.5.
2013-09-05 | GSE49878 | GEO
Project description:Transcriptional profile of mouse nephron progenitor cells
| PRJNA354556 | ENA
Project description:Eya1 interacts with Six1/2 to induce nephron fate and promote nephron progenitor self-renewal. Haploinsufficiency for these genes in humans causes kidney agenesis or hypoplasia. However, how the Eya1-centered network operates remains elusive. Here we identify Eya1's interacting factors via mass-spectrometry and show that Eya1 and Six2 interact with Brg1-based SWI/SNF chromatin-remodeling complex in the kidney. Depletion of Brg1 results in lack of metanephric mesenchyme and depletion of nephron progenitor cells, which is linked to loss of Eya1 expression. Transcriptional profiling reveals conspicuous downregulation of the proto-oncogene Pbx1 and the Dchs1/Fat4 signaling but premature upregulation of a large subset of genes for podocyte lineages and aberrant activation of oncogenic factors in Brg1-deficent cell. ChIP-seq identifies Brg1-occupancy to enhancers at Pbx1 to a distal enhancer of Eya1 that drives nephron progenitor-specific expression. We demonstrate Six2-dependent Brg1 enrichment to the proximal-promoter of Mycn and two distal enhancers of Pbx1, all of which govern nephron progenitor-specific expression in response to binding to Six2. Together, our results suggest a possible mechanism through which the functional specificity of Brg1-BAFs and Eya1-Six2 in cell cycle regulation and self-renewal of the nephron progenitors may be in part achieved.
2021-10-01 | GSE185050 | GEO