Nephron endowment
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA298245 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2588350.fastq.gz | Fastqsanger.gz | |||
| SRR2588360.fastq.gz | Fastqsanger.gz | |||
| SRR2588710.fastq.gz | Fastqsanger.gz | |||
| SRR2588341.fastq.gz | Fastqsanger.gz | |||
| SRR2588351.fastq.gz | Fastqsanger.gz |
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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: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:Nephron endowment is a key determinant of later life hypertension and kidney disease. Here we studied whether epigenetic changes, specifically the ten–eleven translocation (Tet) DNA demethylase family, Tet1, Tet2, and Tet3-mediated active DNA hydroxymethylation is necessary for gene expression regulation and kidney differentiation. We generated mice with deletion of Tet1, Tet2 or Tet3 in Six2 positive nephron progenitors (NP). We did not observe changes in development or kidney function in mice with nephron progenitor-specific deletion of Tet1, Tet2, Tet3 or Tet1/Tet2 or Tet1/Tet3. On the other hand, mice with combined Tet2 and Tet3 loss in Six2-positive NPCs failed to form nephrons leading to kidney failure and perinatal death. Tet2 and Tet3 loss in Six2-positive NPs resulted in defect in mesenchymal to epithelial transition and renal vesicle differentiation. Whole genome bisulfite sequencing, single cell RNA sequencing, and gene and protein expression assay identified a defect in expression in genes in the WNT-β-catenin signaling pathway in absence of Tet2 and Tet3 due to a failure in demethylation of these loci. Our results indicate the key role of Tet2 and Tet3-mediated active cytosine hydroxymethylation in NPs in kidney development and nephron endowment.
2022-11-23 | GSE212715 | GEO
Project description:Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm infants and children with multi- organ birth defect syndromes that affect the kidney and urinary tract. We created a mouse model of congenital low nephron number due to deletion of Mta2 in nephron progenitor cells. Mta2 is a core component of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. These mice developed albuminuria at 4 weeks of age followed by focal segmental glomerulosclerosis (FSGS) at 8 weeks, with progressive kidney injury and fibrosis. Our studies reveal that altered mitochondrial metabolism in the post-natal period leads to accumulation of neutral lipids in glomeruli at 4 weeks of age followed by reduced mitochondrial oxygen consumption. We found that NuRD cooperated with Zbtb7a/7b to regulate a large number of metabolic genes required for fatty acid oxidation and oxidative phosphorylation. Analysis of human kidney tissue also supported a role for reduced mitochondrial lipid metabolism and ZBTB7A/7B in FSGS and CKD. We propose that an inability to meet the physiological and metabolic demands of post-natal somatic growth of the kidney promotes the transition to CKD in the setting of glomerular hypertrophy due to low nephron endowment.
2023-11-05 | GSE246693 | 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.
2015-02-16 | GSE56253 | GEO
Project description:Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm infants and children with multi- organ birth defect syndromes that affect the kidney and urinary tract. We created a mouse model of congenital low nephron number due to deletion of Mta2 in nephron progenitor cells. Mta2 is a core component of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. These mice developed albuminuria at 4 weeks of age followed by focal segmental glomerulosclerosis (FSGS) at 8 weeks, with progressive kidney injury and fibrosis. Our studies reveal that altered mitochondrial metabolism in the post-natal period leads to accumulation of neutral lipids in glomeruli at 4 weeks of age followed by reduced mitochondrial oxygen consumption. We found that NuRD cooperated with Zbtb7a/7b to regulate a large number of metabolic genes required for fatty acid oxidation and oxidative phosphorylation. Analysis of human kidney tissue also supported a role for reduced mitochondrial lipid metabolism and ZBTB7A/7B in FSGS and CKD. We propose that an inability to meet the physiological and metabolic demands of post-natal somatic growth of the kidney promotes the transition to CKD in the setting of glomerular hypertrophy due to low nephron endowment.
2023-11-05 | GSE246692 | GEO
Project description:Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm infants and children with multi- organ birth defect syndromes that affect the kidney and urinary tract. We created a mouse model of congenital low nephron number due to deletion of Mta2 in nephron progenitor cells. Mta2 is a core component of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. These mice developed albuminuria at 4 weeks of age followed by focal segmental glomerulosclerosis (FSGS) at 8 weeks, with progressive kidney injury and fibrosis. Our studies reveal that altered mitochondrial metabolism in the post-natal period leads to accumulation of neutral lipids in glomeruli at 4 weeks of age followed by reduced mitochondrial oxygen consumption. We found that NuRD cooperated with Zbtb7a/7b to regulate a large number of metabolic genes required for fatty acid oxidation and oxidative phosphorylation. Analysis of human kidney tissue also supported a role for reduced mitochondrial lipid metabolism and ZBTB7A/7B in FSGS and CKD. We propose that an inability to meet the physiological and metabolic demands of post-natal somatic growth of the kidney promotes the transition to CKD in the setting of glomerular hypertrophy due to low nephron endowment.
2023-11-05 | GSE246694 | GEO
Project description:To investigate the lncRNA profiles in low birth weight rats with reduced nephron endowment induced by restriction of maternal protein intake. Low birth weight by reduced nephron endowment is a risk factor for hypertension and end-stage renal disease in adulthood.
2017-02-13 | GSE64239 | GEO
Project description:Nephron endowment is determined by the self-renewal and induction of a nephron progenitor pool established at the onset of kidney development. In the mouse, the related transcriptional regulators Six1 and Six2 play non-overlapping roles in nephron progenitors. Transient Six1 activity prefigures, and is essential for, active nephrogenesis. In contrast, Six2 maintains later progenitor self-renewal from the onset of nephrogenesis. We compared Six2’s regulatory actions in mouse and human nephron progenitors by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Surprisingly, SIX1 was identified as a SIX2 target unique to the human nephron progenitors. Further, RNA-seq and immunostaining revealed overlapping SIX1 and SIX2 progenitor activity in the 16 week human fetal kidney. Human SIX1 ChIP-seq revealed a similar set of targets to SIX2, and predicted both factors bind DNA through an identical recognition site. In contrast to the mouse where Six2 binds its own enhancers but doesn’t interact with DNA around Six1, both human SIX1 and SIX2 bind homologous SIX2 enhancers and putative enhancers positioned around SIX1. Transgenic analysis of a putative human SIX1 enhancer in the mouse revealed a transient, mouse-like, pre-nephrogenic, Six1 regulatory pattern. Together, these data demonstrate a divergence in SIX-factor regulation between mouse and human nephron progenitors. In the human, an auto/cross-regulatory loop drives continued SIX1 and SIX2 expression during active nephrogenesis. In contrast, the mouse establishes only an auto-regulatory Six2 loop. It is tempting to speculate that differential SIX-factor regulation may contribute to species differences in the duration of progenitor programs and nephron output.
2016-01-31 | GSE73866 | GEO