Rhythmic nephron formation in the developing kidney [E17_NZC_scRNAseq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE315095 | GEO | 2026/01/06
REPOSITORIES: GEO
Similar Datasets
Project description:The mammalian kidney achieves massive parallelization of function by exponentially duplicating nephron-forming niches during development. Each niche caps a tip of the ureteric bud epithelium (the future urinary collecting duct tree) as it undergoes branching morphogenesis, while nephron progenitors within niches balance self-renewal and differentiation to early nephron cells. Nephron formation rate approximately matches branching rate over a large fraction of mouse gestation, yet the nature of this apparent pace-maker is unknown. Here we correlate spatial transcriptomics data with branching ‘life-cycle’ to discover rhythmically alternating signatures of nephron progenitor differentiation and renewal across Wnt, Hippo/Yap, retinoic acid (RA), and other pathways. Our data bring temporal resolution to the renewal vs. differentiation balance in the nephrogenic niche and inform new strategies to achieve self-sustaining nephron formation in synthetic human kidney tissues.
2026-01-06 | GSE315096 | GEO
Project description:The mammalian kidney achieves massive parallelization of function by exponentially duplicating nephron-forming niches during development. Each niche caps a tip of the ureteric bud epithelium (the future urinary collecting duct tree) as it undergoes branching morphogenesis, while nephron progenitors within niches balance self-renewal and differentiation to early nephron cells. Nephron formation rate approximately matches branching rate over a large fraction of mouse gestation, yet the nature of this apparent pace-maker is unknown. Here we correlate spatial transcriptomics data with branching ‘life-cycle’ to discover rhythmically alternating signatures of nephron progenitor differentiation and renewal across Wnt, Hippo/Yap, retinoic acid (RA), and other pathways. Our data bring temporal resolution to the renewal vs. differentiation balance in the nephrogenic niche and inform new strategies to achieve self-sustaining nephron formation in synthetic human kidney tissues.
2026-01-06 | GSE315094 | GEO
Project description:The mammalian kidney achieves massive parallelization of function by exponentially duplicating nephron-forming niches during development. Each niche caps a tip of the ureteric bud epithelium (the future urinary collecting duct tree) as it undergoes branching morphogenesis, while nephron progenitors within niches balance self-renewal and differentiation to early nephron cells. Nephron formation rate approximately matches branching rate over a large fraction of mouse gestation, yet the nature of this apparent pace-maker is unknown. Here we correlate spatial transcriptomics data with branching ‘life-cycle’ to discover rhythmically alternating signatures of nephron progenitor differentiation and renewal across Wnt, Hippo/Yap, retinoic acid (RA), and other pathways. Our data bring temporal resolution to the renewal vs. differentiation balance in the nephrogenic niche and inform new strategies to achieve self-sustaining nephron formation in synthetic human kidney tissues.
2026-01-06 | GSE315435 | GEO
Project description:Maintaining adequate nephron number is crucial for normal kidney function, as even slight deficits can predispose individuals to hypertension and other late-onset renal diseases. Congenital anomalies of the kidney and urinary tract arise from abnormal embryonic kidney development, which involves the coordinated reciprocal induction of the ureteric bud and metanephric mesenchyme. Preserving the balance between self-renewal and differentiation of nephron progenitor cells in the metanephric mesenchyme is essential for nephron endowment. Prior work has implicated histone modifications in regulating kidney lineage-specific gene transcription and nephron endowment. Here, we selectively inactivated the H3K4 methyltransferase complex component ASH2L in mouse nephron progenitor cells to elucidate its role in nephron progenitor cell self-renewal and differentiation. The results showed that Ash2l inactivation disrupted H3K4 trimethylation establishment at promoters of genes controlling nephron progenitor cell stemness, differentiation, and cell cycle, leading to premature nephron progenitor cell depletion, cell cycle arrest, and abnormal differentiation of early nephron progenitors, resulting in renal dysplasia at birth. These findings identify ASH2L-mediated H3K4 methylation as a critical epigenetic regulator of kidney development and suggest a novel mechanism contributing to congenital anomalies of the kidney and urinary tract. This knowledge may guide future efforts to unravel the pathogenesis of these conditions and develop targeted therapies.
2025-01-09 | GSE269088 | GEO
Project description:Maintaining adequate nephron number is crucial for normal kidney function, as even slight deficits can predispose individuals to hypertension and other late-onset renal diseases. Congenital anomalies of the kidney and urinary tract arise from abnormal embryonic kidney development, which involves the coordinated reciprocal induction of the ureteric bud and metanephric mesenchyme. Preserving the balance between self-renewal and differentiation of nephron progenitor cells in the metanephric mesenchyme is essential for nephron endowment. Prior work has implicated histone modifications in regulating kidney lineage-specific gene transcription and nephron endowment. Here, we selectively inactivated the H3K4 methyltransferase complex component ASH2L in mouse nephron progenitor cells to elucidate its role in nephron progenitor cell self-renewal and differentiation. The results showed that Ash2l inactivation disrupted H3K4 trimethylation establishment at promoters of genes controlling nephron progenitor cell stemness, differentiation, and cell cycle, leading to premature nephron progenitor cell depletion, cell cycle arrest, and abnormal differentiation of early nephron progenitors, resulting in renal dysplasia at birth. These findings identify ASH2L-mediated H3K4 methylation as a critical epigenetic regulator of kidney development and suggest a novel mechanism contributing to congenital anomalies of the kidney and urinary tract. This knowledge may guide future efforts to unravel the pathogenesis of these conditions and develop targeted therapies.
2025-01-09 | GSE269089 | 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: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:Early human kidney development is poorly documented due to tissue inaccessibility and a lack of genetic tractability. Here we combine reprogramming, CRISPR/Cas9 gene-editing and organoid technologies to study the nephron lineage in a human context. We confirm the presence of a SIX2+ population in early kidney organoids with a transcriptional profile akin to human fetal nephron progenitors. Using lineage-tracing analyses, we show that SIX2-expressing cells contribute to nephron formation but not to the putative collecting duct epithelium. Labeling of SIX2+ cells at various time-points during organoid differentiation revealed a markedly reduced capacity for these cells to contribute to nephron formation over time. This suggests human kidney organoids lack a true nephron progenitor niche, as the developing kidney does in vivo, capable of both self-renewal and ongoing nephrogeneis. Nonetheless, human iPSC-derived kidney tissue maintains previously identified lineage relationships, which supports the utility of in vitro organoid models for interrogating the molecular and cellular basis of early human development.
2019-03-12 | GSE119561 | 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:Nephron number is a major determinant of long-term renal function. We hypothesized a link between epigenetic regulation and nephron formation. In support of this hypothesis, expression analysis evidenced high levels of DNA methyltransferases Dnmt1 and Dnmt3a in the nephrogenic zone of the developing mouse kidney. Using targeted loss-of-function manipulations in mice, we show that deletion of Dnmt1 in nephron progenitor cells results in a marked hypoplasia and reduction of nephron number at birth. In contrast, deletion of Dnmt3a/3b in nephron progenitor cells or deletion of Dnmt1/3a/3b in differentiated renal cells did not lead to any overt kidney phenotype. Whole mount optical projection tomography and 3D-reconstructions uncovered a significant reduction of stem cell niches and progenitor cells in Dnmt1-deficient mice. Ultimately, RNA sequencing analysis revealed that Dnmt1 controls DNA transcription regulating progenitor renewal, identity and differentiation. In summary, this study establishes DNA methylation as key regulatory event of prenatal renal programming.
2019-11-15 | GSE94089 | GEO