Nephron progenitor commitment is a stochastic process influenced by cell migration.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA485769 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7689140_1.fastq.gz | Fastqsanger.gz | |||
| SRR7689140_2.fastq.gz | Fastqsanger.gz | |||
| SRR7689141_1.fastq.gz | Fastqsanger.gz | |||
| SRR7689141_2.fastq.gz | Fastqsanger.gz | |||
| SRR7689139_1.fastq.gz | Fastqsanger.gz |
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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:Progenitor self-renewal and differentiation is often regulated by spatially restricted cues within a tissue microenvironment. Here, we examine how progenitor cell migration impacts regionally induced commitment within the nephrogenic niche in mice. We identify a subset of cells that express Wnt4, an early marker of nephron commitment, but migrate back into the progenitor population where they accumulate over time. Single cell RNA-seq and computational modelling of returning cells reveals that nephron progenitors can traverse the transcriptional hierarchy between self-renewal and commitment in either direction. This plasticity may enable robust regulation of nephrogenesis as niches remodel and grow during organogenesis.
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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:During mammalian kidney development, mesenchymal nephron progenitors (cap mesenchyme) differentiate into the epithelial cells that go on to form the nephron. Although differentiation of nephron progenitors is triggered by activation of Wnt/b-catenin signaling, constitutive activation of Wnt/b-catenin signaling blocks epithelialization of nephron progenitors. Full epithelialization of nephron progenitors requires transient activation of Wnt/b-catenin signaling. We performed transcriptional profiling of nephron progenitors responding to constitutive or transient activation of Wnt/b-catenin signaling. Nephron progenitors were FACS-isolated from BAC transgenic Six2GFPcre-positive embryonic kidneys at E16.5. Cells were aggregated by centrifugation at 850g for 5min and incubated in 10%FBS/DMEM containing either 4uM BIO or the equal volume of DMSO for 24hrs or 48hrs.
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Project description:Purpose: To use single-cell RNA-Seq analysis of nephron progenitors in order to determine transcrptional differences as nephron progenitors age. Methods: Using a combination of FACS sorting and a Fluidigm Single-cell auto-prep system, we generated high-throughput RNA-SEQ data of nephron progenitors during development Results: Single cells transcriptome profiling of nephron progenitors revealed progressive age-dependent changes with heterogeneity increasing in older populations. 96-single cell transcriptomes were determined from nephron progenitors of e14.5, e18.5 and P0 using Cited1GFP transgenic animals
2015-12-23 | E-GEOD-66202 | 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. 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:Self-renewing undifferentiated nephron progenitors express Six2, a transcription factor that is required for their maintenance as undifferentiated progenitors. Differentiation of nephron progenitors is triggered by Wnt/b-catenin signaling. In order to understand how Six2 and Wnt signaling counteract each other, we performed ChIP-seq of Six2 and b-catenin in mesenchymal nephron progenitor cells. Nephron progenitors were FACS-isolated from BAC transgenic Six2GFPcre-positive embryonic kidneys at E16.5. For Six2 ChIP, freshly FACS isolated Six2+ cells were used. For b-catenin ChIP, FACS isolated Six2+ cells were aggregated by centrifugation at 850g for 5min and incubated in 10%FBS/DMEM containing 4uM BIO for 24hrs.
2012-09-11 | E-GEOD-39837 | biostudies-arrayexpress