Defects in nephrogenesis result in an expansion of the Foxd1+ stromal progenitor population
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ABSTRACT:
PROVIDER: PRJNA1224207 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32358467.fastq.gz | Fastqsanger.gz | |||
| SRR32358468.fastq.gz | Fastqsanger.gz | |||
| SRR32358469.fastq.gz | Fastqsanger.gz | |||
| SRR32358470.fastq.gz | Fastqsanger.gz | |||
| SRR32358471.fastq.gz | Fastqsanger.gz |
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Project description:Reciprocal signaling interactions coordinate multiple aspects of kidney development. While signals from the stroma have been shown to regulate nephron progenitor cell (NPC) differentiation, much less is known about regulation of the stromal progenitor population. We sought to further examine how defects in the nephron lineage may non-autonomously affect stromal development. To aid in this analysis, we generated single nuclei RNA-seq using 10x genomics from paired E15.5 control kidneys (cre-negative and Six2creTGC) and mutant kidneys (Six2cre;Wt1c/c) to identify additional markers and gene expression changes of the Foxd1+ stromal progenitor population at this timepoint, and validated the expression of early B cell factor 3 (Ebf3), aldehyde oxidase 3 (Aox3), fibroblast activation protein (Fap), insulin growth factor 1 (Igf1), and glutamate ionotropic receptor AMPA type subunit 1 (Gria1) in control and mutant kidneys.
2025-02-22 | GSE289696 | GEO
Project description:Reciprocal signaling interactions coordinate multiple aspects of kidney development. While signals from the stroma have been shown to regulate nephron progenitor cell (NPC) differentiation, much less is known about regulation of the stromal progenitor population. Here, we demonstrate that disruption of the NPC lineage via loss of Wt1 (i.e., Six2cre;Wt1 c/c ) results in an expansion of Foxd1+ stromal progenitor cells. Analyses of the developing stroma in two additional models, including Wnt4-null mutants (which fail to form nephron structures similar to Six2cre;Wt1 c/c kidneys) and NPC ablation via diphtheria toxin (i.e., Six2cre;RosaDTA c/+ ), both phenocopy Six2cre;Wt1 c/c mutants, thus further confirming that defects in the NPC lineage result in abnormal development of the stromal progenitor population. Furthermore, we identify a subcluster of the Foxd1+ stroma that appears expanded in the three mutant mouse models and conserved in human fetal kidneys. Overall, the findings from this study suggest that loss of differentiating nephron structures may result in possible over proliferation of the stromal progenitor population and/or a block in stromal differentiation and further highlight how crosstalk amongst the progenitor cell lineages coordinates multiple aspects of kidney development.
| S-EPMC11844377 | biostudies-literature
Project description:Hotspot gain-of-function mutations in the YEATS domain of the histone reader protein ENL have been identified in Wilms’ tumor. To investigate the pathogenic role of these cancer-associated ENL mutations in kidney development and tumorigenesis in vivo, we generated conditional knock-in mouse models mimicking patient-derived ENL YEATS mutations. Mice with heterozygous expression of ENLT mutants in either Six2+ nephrogenic or Foxd1+ stromal lineage exhibit severe yet distinct defects in kidney development, both resulting in neonatal lethality. The Six2-ENLT mutant kidney rudiments display compromised cap mesenchyme, scant proximal tubules and cystic glomeruli, indicative of premature commitment and differentiation blockade during nephrogenesis. Bulk and spatial transcriptomic analyses uncover aberrant activation of Hox genes and genes involved in cell fate commitment, especially the Wnt signaling pathway, in ENLT mutant-expressing nephrogenic cells. In contrast, the Foxd1-ENLT mutant kidneys exhibit expansion in renal capsule and cap mesenchyme, accompanied with dysregulation of stromal genes involved in nephrogenesis and stroma-nephron crosstalk. Collectively, our study sheds lights on how ENL YEATS domain mutations impede nephrogenesis through different pathways in nephrogenic and stromal lineages, paving the way for further investigations into their roles in tumorigenesis.
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Project description:Hotspot gain-of-function mutations in the YEATS domain of the histone reader protein ENL have been identified in Wilms’ tumor. To investigate the pathogenic role of these cancer-associated ENL mutations in kidney development and tumorigenesis in vivo, we generated conditional knock-in mouse models mimicking patient-derived ENL YEATS mutations. Mice with heterozygous expression of ENLT mutants in either Six2+ nephrogenic or Foxd1+ stromal lineage exhibit severe yet distinct defects in kidney development, both resulting in neonatal lethality. The Six2-ENLT mutant kidney rudiments display compromised cap mesenchyme, scant proximal tubules and cystic glomeruli, indicative of premature commitment and differentiation blockade during nephrogenesis. Bulk and spatial transcriptomic analyses uncover aberrant activation of Hox genes and genes involved in cell fate commitment, especially the Wnt signaling pathway, in ENLT mutant-expressing nephrogenic cells. In contrast, the Foxd1-ENLT mutant kidneys exhibit expansion in renal capsule and cap mesenchyme, accompanied with dysregulation of stromal genes involved in nephrogenesis and stroma-nephron crosstalk. Collectively, our study sheds lights on how ENL YEATS domain mutations impede nephrogenesis through different pathways in nephrogenic and stromal lineages, paving the way for further investigations into their roles in tumorigenesis.
2025-02-20 | GSE266256 | GEO
Project description:Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. Foxd1 is required during kidney development and its inactivation results in failure of nephron progenitor cell differentiation. Foxd1 is expressed in interstitial cells adjacent to nephron progenitor cells, suggesting an essential role for the progenitor cell niche in nephrogenesis. To better understand how cortical interstitial cells in general, and FOXD1 in particular, influence the progenitor cell niche, we examined the differentiation states of two progenitor cell subtypes in Foxd1-/- tissue. We found that while nephron progenitor cells are retained in a primitive CITED1-expressing compartment, cortical interstitial cells prematurely differentiate. To identify pathways regulated by FOXD1, we used microarray analysis and screened for target genes by comparison of Foxd1 null and wild type tissues. We chose the E14.5 timepoint because at this stage nephron differentiation is present in wild type kidneys but absent from Foxd1 null kidneys. We examined genes that were upregulated or downregulated in the Foxd1 null compared to wild type. Embryonic kidneys were harvested from Foxd1-/- and wild type littermates from three E14.5 litters. Three biological replicates were generated per genotype, each containing two non-littermate kidney pairs. Sex of embryos was not determined.
2013-11-14 | E-GEOD-52354 | biostudies-arrayexpress
Project description:Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. Foxd1 is required during kidney development and its inactivation results in failure of nephron progenitor cell differentiation. Foxd1 is expressed in interstitial cells adjacent to nephron progenitor cells, suggesting an essential role for the progenitor cell niche in nephrogenesis. To better understand how cortical interstitial cells in general, and FOXD1 in particular, influence the progenitor cell niche, we examined the differentiation states of two progenitor cell subtypes in Foxd1-/- tissue. We found that while nephron progenitor cells are retained in a primitive CITED1-expressing compartment, cortical interstitial cells prematurely differentiate. To identify pathways regulated by FOXD1, we used microarray analysis and screened for target genes by comparison of Foxd1 null and wild type tissues. We chose the E14.5 timepoint because at this stage nephron differentiation is present in wild type kidneys but absent from Foxd1 null kidneys. We examined genes that were upregulated or downregulated in the Foxd1 null compared to wild type.
2013-11-14 | GSE52354 | GEO
Project description:It remains unclear how the ectopic expression of defined transcription factors induces dynamic changes in gene expression profiles that establish a pluripotent state during direct cell reprogramming. In the present study, we first identified a temporal gene expression program during the reprogramming process. Promoter analyses then predicted the role of two forkhead box transcription factors, Foxd1 and Foxo1, as mediators of the gene expression program. Knockdown of Foxd1 or Foxo1 reduced the number of induced pluripotent stem cells (iPSCs). The knockout of Foxd1 prevented the downstream transcription program, including the expression of reprogramming marker genes. Interestingly, the expression level of Foxd1 was also transiently increased in a small population of cells in the middle stage of reprogramming. The presence or absence of Foxd1 expression in this stage was correlated with a future cell fate as iPSCs or non-reprogrammed cells. These results suggest that Foxd1 is a mediator and indicator of the successful progression of the gene expression program in cell reprogramming. Mouse embryonic fibroblasts (MEFs) of Foxd1+/+, Foxd1+/- or Foxd1-/- were infected with retroviruses encoding the three transcription factors (Oct4, Sox2 and Klf4) at day 0 and sampled at day 8.
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Project description:It remains unclear how the ectopic expression of defined transcription factors induces dynamic changes in gene expression profiles that establish a pluripotent state during direct cell reprogramming. In the present study, we first identified a temporal gene expression program during the reprogramming process. Promoter analyses then predicted the role of two forkhead box transcription factors, Foxd1 and Foxo1, as mediators of the gene expression program. Knockdown of Foxd1 or Foxo1 reduced the number of induced pluripotent stem cells (iPSCs). The knockout of Foxd1 prevented the downstream transcription program, including the expression of reprogramming marker genes. Interestingly, the expression level of Foxd1 was also transiently increased in a small population of cells in the middle stage of reprogramming. The presence or absence of Foxd1 expression in this stage was correlated with a future cell fate as iPSCs or non-reprogrammed cells. These results suggest that Foxd1 is a mediator and indicator of the successful progression of the gene expression program in cell reprogramming.
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Project description:Cell senescence is a driver of various aging-associated disorders including osteoarthritis. Here, we identified a critical role for Yes-associated protein (YAP), a major effector of Hippo signaling, in maintaining a younger state of human mesenchymal stem cells (MSCs) and ameliorating osteoarthritis in mice. Targeted knockout of YAP in hMSCs resulted in premature cellular senescence. Mechanistically, YAP interacted with TEA domain transcriptional factor (TEAD) to activate forkhead box D1 (FOXD1) expression. YAP deficiency led to the downregulation of FOXD1, a geroprotective protein. In turn, overexpression of YAP or FOXD1 rejuvenated aged hMSCs. Moreover, intra-articular administration of lentiviral vectors encoding YAP or FOXD1 attenuated the development of osteoarthritis in mice. Collectively, our findings reveal YAP-FOXD1, a novel aging-associated regulatory axis, as a potential therapeutic target for gene therapy to alleviate osteoarthritis.
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