Browse
Submit Data
Databases
API
Help

Dataset Information

30 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Stromal β-catenin activation impacts nephron progenitor differentiation in the developing kidney and may contribute to Wilms tumor.

ABSTRACT: Wilms' tumor (WT) morphologically resembles the embryonic kidney, consisting of blastema, epithelial and stromal components, suggesting tumors arise from the dysregulation of normal development. β-Catenin activation is observed in a significant proportion of WTs; however, much remains to be understood about how it contributes to tumorigenesis. Although activating β-catenin mutations are observed in both blastema and stromal components of WT, current models assume that activation in the blastemal lineage is causal. Paradoxically, studies performed in mice suggest that activation of β-catenin in the nephrogenic lineage results in loss of nephron progenitor cell (NPC) renewal, a phenotype opposite to WT. Here, we show that activation of β-catenin in the stromal lineage non-autonomously prevents the differentiation of NPCs. Comparisons of the transcriptomes of kidneys expressing an activated allele of β-catenin in the stromal or nephron progenitor cells reveals that human WT more closely resembles the stromal-lineage mutants. These findings suggest that stromal β-catenin activation results in histological and molecular features of human WT, providing insights into how alterations in the stromal microenvironment may play an active role in tumorigenesis.

SUBMITTER: Drake KA

PROVIDER: S-EPMC7406317 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Stromal beta-catenin activation impacts nephron progenitor differentiation in the developing kidney and may contribute to Wilms tumor

Project description:Wilms tumor (WT) morphologically resembles the embryonic kidney, consisting of blastema, epithelial, and stromal components, suggesting tumors arise from the dysregulation of normal development. Activation of beta-catenin is observed in a significant proportion of human WTs; however, much remains to be understood about how it contributes to tumorigenesis. While activating beta-catenin mutations are observed in both blastema and stromal components of human WT, current models assume that activation in the blastemal lineage is causal. Paradoxically, studies performed in mice suggest that activation of b-catenin in this lineage results in loss of nephron progenitor cell (NPC) renewal, a phenotype opposite to WT. Here, we show that activation of beta-catenin in the stromal lineage acts non-autonomously, resulting in expansion of NPCs and an inhibition of differentiation. Comparisons of the transcriptomes of kidneys expressing an activated allele of beta-catenin in the stromal or nephron progenitor cells reveals that human WT more closely resembles the stromal-lineage mutants. These findings suggest that stromal beta-catenin activation results in histological and molecular features of human WT, providing insights into how stroma signaling may play an active role in tumorigenesis.

2020-05-08 | GSE150074 | GEO

Stromal beta-catenin activation impacts nephron progenitor differentiation in the developing kidney and may contribute to Wilms tumor

Project description:Stromal beta-catenin activation impacts nephron progenitor differentiation in the developing kidney and may contribute to Wilms tumor

| PRJNA631035 | ENA

Nephron Progenitor But Not Stromal Progenitor Cells Give Rise to Wilms Tumors in Mouse Models with ?-Catenin Activation or Wt1 Ablation and Igf2 Upregulation.

Project description:Wilms tumor, a common childhood tumor of the kidney, is thought to arise from undifferentiated renal mesenchyme. Variable tumor histology and the identification of tumor subsets displaying different gene expression profiles suggest that tumors may arise at different stages of mesenchyme differentiation and that this ontogenic variability impacts tumor pathology, biology, and clinical outcome. To test the tumorigenic potential of different cell types in the developing kidney, we used kidney progenitor-specific Cre recombinase alleles to introduce Wt1 and Ctnnb1 mutations, two alterations observed in Wilms tumor, into embryonic mouse kidney, with and without biallelic Igf2 expression, another alteration that is observed in a majority of tumors. Use of a Cre allele that targets nephron progenitors to introduce a Ctnnb1 mutation that stabilizes ?-catenin resulted in the development of tumors with a predominant epithelial histology and a gene expression profile in which genes characteristic of early renal mesenchyme were not expressed. Nephron progenitors with Wt1 ablation and Igf2 biallelic expression were also tumorigenic but displayed a more triphasic histology and expressed early metanephric mesenchyme genes. In contrast, the targeting of these genetic alterations to stromal progenitors did not result in tumors. These data demonstrate that committed nephron progenitors can give rise to Wilms tumors and that committed stromal progenitors are less tumorigenic, suggesting that human Wilms tumors that display a predominantly stromal histology arise from mesenchyme before commitment to a stromal lineage.

| S-EPMC5005262 | biostudies-literature

Genomic characterization of Wilms' tumor suppressor 1 targets in nephron progenitor cells during kidney development.

Project description:The Wilms' tumor suppressor 1 (WT1) gene encodes a DNA- and RNA-binding protein that plays an essential role in nephron progenitor differentiation during renal development. To identify WT1 target genes that might regulate nephron progenitor differentiation in vivo, we performed chromatin immunoprecipitation (ChIP) coupled to mouse promoter microarray (ChIP-chip) using chromatin prepared from embryonic mouse kidney tissue. We identified 1663 genes bound by WT1, 86% of which contain a previously identified, conserved, high-affinity WT1 binding site. To investigate functional interactions between WT1 and candidate target genes in nephron progenitors, we used a novel, modified WT1 morpholino loss-of-function model in embryonic mouse kidney explants to knock down WT1 expression in nephron progenitors ex vivo. Low doses of WT1 morpholino resulted in reduced WT1 target gene expression specifically in nephron progenitors, whereas high doses of WT1 morpholino arrested kidney explant development and were associated with increased nephron progenitor cell apoptosis, reminiscent of the phenotype observed in Wt1(-/-) embryos. Collectively, our results provide a comprehensive description of endogenous WT1 target genes in nephron progenitor cells in vivo, as well as insights into the transcriptional signaling networks controlled by WT1 that might direct nephron progenitor fate during renal development.

| S-EPMC2835332 | biostudies-literature

FOXD1 promotes nephron progenitor differentiation by repressing decorin in the embryonic kidney.

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 although nephron progenitor cells are retained in a primitive CITED1-expressing compartment, cortical interstitial cells prematurely differentiate. To identify pathways regulated by FOXD1, we screened for target genes by comparison of Foxd1 null and wild-type tissues. We found that the gene encoding the small leucine-rich proteoglycan decorin (DCN) is repressed by FOXD1 in cortical interstitial cells, and we show that compound genetic inactivation of Dcn partially rescues the failure of progenitor cell differentiation in the Foxd1 null. We demonstrate that DCN antagonizes BMP/SMAD signaling, which is required for the transition of CITED1-expressing nephron progenitor cells to a state that is primed for WNT-induced epithelial differentiation. On the basis of these studies, we propose a mechanism for progenitor cell retention in the Foxd1 null in which misexpressed DCN produced by prematurely differentiated interstitial cells accumulates in the extracellular matrix, inhibiting BMP7-mediated transition of nephron progenitor cells to a compartment in which they can respond to epithelial induction signals.

| S-EPMC3865747 | biostudies-literature

Stromal-epithelial crosstalk regulates kidney progenitor cell differentiation.

Project description:Present models suggest that the fate of the kidney epithelial progenitors is solely regulated by signals from the adjacent ureteric bud. The bud provides signals that regulate the survival, renewal and differentiation of these cells. Recent data suggest that Wnt9b, a ureteric-bud-derived factor, is sufficient for both progenitor cell renewal and differentiation. How the same molecule induces two seemingly contradictory processes is unknown. Here, we show that signals from the stromal fibroblasts cooperate with Wnt9b to promote differentiation of the progenitors. The atypical cadherin Fat4 encodes at least part of this stromal signal. Our data support a model whereby proper kidney size and function is regulated by balancing opposing signals from the ureteric bud and stroma to promote renewal and differentiation of the nephron progenitors.

| S-EPMC3891676 | biostudies-literature

The PI3K pathway balances self-renewal and differentiation of nephron progenitor cells through ?-catenin signaling.

Project description:Nephron progenitor cells differentiate to form nephrons during embryonic kidney development. In contrast, self-renewal maintains progenitor numbers and premature depletion leads to impaired kidney function. Here we analyze the PI3K pathway as a point of convergence for the multiple pathways that are known to control self-renewal in the kidney. We demonstrate that a reduction in PI3K signaling triggers premature differentiation of the progenitors and activates a differentiation program that precedes the mesenchymal-to-epithelial transition through ectopic activation of the ?-catenin pathway. Therefore, the combined output of PI3K and other pathways fine-tunes the balance between self-renewal and differentiation in nephron progenitors.

| S-EPMC4400645 | biostudies-literature

Role for compartmentalization in nephron progenitor differentiation.

Project description:Embryonic nephron progenitor cells are segregated in molecularly distinct compartments of unknown function. Our study reveals an integral role for bone morphogenetic protein-SMAD in promoting transition of progenitors from the primitive Cbp/p300-interacting transactivator 1 expressing (CITED1+) compartment to the uniquely sine oculis-related homeobox 2 expressing (SIX2-only) compartment where they become inducible by wingless-type mouse mammary tumor virus integration site family member (WNT)/β-catenin signaling. Significantly, CITED1(+) cells are refractory to WNT/β-catenin induction. We propose a model in which the primitive CITED1(+) compartment is refractory to induction by WNT9b/β-catenin, ensuring maintenance of undifferentiated progenitor cells for future nephrogenesis. Bone morphogenetic protein 7-SMAD is then required for transition to a distinct compartment in which cells become inducible by WNT9b/β-catenin, allowing them to progress toward epithelialization.

| S-EPMC3607044 | biostudies-literature

Nephron, Wilms' tumor-1 (WT1), and synaptopodin expression in developing podocytes of mice.

Project description:Newborn mouse glomeruli are still immature with a morphological feature of an early capillary loop stage, but infant mice do not manifest proteinuria. Little is known about the molecular mechanism whereby infant mice are resistant to proteinuria. Nephrin and synaptopodin are crucial for slit diaphragm and foot process (FP) formation for avoiding proteinuria. Nephrin tyrosine phosphorylation means a transient biological signaling required for FP repair or extension during nephrotic disease. Using an immunohistochemical technique, we examined the natural course of nephrin, Wilms' tumor-1 (WT1) and synaptopodin at 16.5 days of embryonic age (E16.5d) and E19.5d, 7 days of post-neonatal age (P7d) and P42d during renal development of mice. As a result, nephrin and synaptopodin were detected at E19.5d in S-shaped bodies. WT1, a transcriptional factor for nephrin, was detected in nucleus in podocyte-like cells in all stages. Nephrin tyrosine phosphorylation was evident in glomeruli at P7d, and this was associated with an early-stage of FP extension. Inversely, nephrin phosphorylation became faint at P42d, along with maturated FP. Based on the present results, we suggest the sequential molecular mechanism to protect growing mice from proteinuria: (i) WT1-induced nephrin production by podocytes in S-shaped bodies at E19.5d; (ii) Synchronized induction of synaptopodin at the same period; and (iii) FP extension is initiated at a milk-suckling stage under a nephrin tyrosine-phosphorylated condition, while it is arrested at an adult stage, associated with a loss of nephrin-based signaling.

| S-EPMC5543238 | biostudies-other

Cep120 is essential for kidney stromal progenitor cell growth and differentiation.

Project description:Mutations in genes that disrupt centrosome structure or function can cause congenital kidney developmental defects and lead to fibrocystic pathologies. Yet, it is unclear how defective centrosome biogenesis impacts renal progenitor cell physiology. Here, we examined the consequences of impaired centrosome duplication on kidney stromal progenitor cell growth, differentiation, and fate. Conditional deletion of the ciliopathy gene Cep120, which is essential for centrosome duplication, in the stromal mesenchyme resulted in reduced abundance of interstitial lineages including pericytes, fibroblasts and mesangial cells. These phenotypes were caused by a combination of delayed mitosis, activation of the mitotic surveillance pathway leading to apoptosis, and changes in both Wnt and Hedgehog signaling that are key for differentiation of stromal cells. Cep120 ablation resulted in small hypoplastic kidneys with medullary atrophy and delayed nephron maturation. Finally, Cep120 and centrosome loss in the interstitium sensitized kidneys of adult mice, causing rapid fibrosis after renal injury via enhanced TGF-β/Smad3-Gli2 signaling. Our study defines the cellular and developmental defects caused by loss of Cep120 and aberrant centrosome biogenesis in the embryonic kidney stroma.

| S-SCDT-10_1038-S44319-023-00019-Z | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data