Stabilization of ß-catenin during murine Kidney Development
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE20325 | GEO | 2011/03/28
SECONDARY ACCESSION(S): PRJNA125389
REPOSITORIES: GEO
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Project description:We define a pathogenic role for a ß-catenin-activated genetic pathway in murine renal dysplasia. Cre-mediated stabilization of ß-catenin in the ureteric cell lineage prior to the onset of kidney development increased ß-catenin levels and caused renal aplasia or severe hypodysplasia. A genome-wide analysis of mRNA expression in dysplastic tissue identified down-regulation of genes required for ureteric branching and up regulation of Tgfß2 and Dkk1. Hoxb7-Cre:EGFP mice ( Zhao, et al. (2004) Dev Biol 276:403-415) were crossed with mice containing loxP sites flanking exon 3 of the ß-catenin allele (ß-catdelta3/delta3) (Harada,et al. (2002) Cancer Res 62:1971-1977) to generate ß-catenin gain-of-function mutant mice specific to the uteric bud, termed ß-catGOF-UB .Eighteen ß-catGOF-UB mutant kidneys and 9 WT kidneys were micro-dissected at E12.5. Mutant kidneys were divided into three random pools (n=3) consisting of 6 kidneys each and mRNA expression assessed by microarray.
2011-03-28 | E-GEOD-20325 | biostudies-arrayexpress
Project description:Grb2 is a small SH2-SH3 adaptor molecule that interacts with activated tyrosine kinase receptors (RTKs), providing a crucial link towards downstream activation of pro-proliferative and pro-survival ERK and Akt signaling pathways. Ret and FGFR2, two RTKs that interact with Grb2, play important roles in ureteric branching and the proper establishment of the renal collecting duct system, but it is unclear whether Grb2 is required in this process. In this study, we selectively ablated a conditional floxed allele of the Grb2 gene within the ureteric epithelial lineage in mice and demonstrate that Grb2 signaling is essentially required for proper collecting duct development. Ureteric Grb2 deficiency results in perinatal lethality and severe renal hypodysplasia closely reminiscent of the rudimentary kidney phenotypes observed in Ret-null mutant mice. Grb2 loss attenuates ERK and Akt activation in the ureteric epithelia resulting in pronounced impairment of ureteric branching. Gene expression analysis reveals that Grb2 deficiency results in defective induction of genes implicated in both ureteric branching and reciprocal mesenchymal metanephric induction. Our findings therefore strongly indicate that Grb2 is a physiologically-relevant major RTK signaling relay partner that promotes renal branching morphogenesis and the proper development of the collecting duct system and the urogenital tract. Microarray was used to profile and compare the transcriptomes of developing kidneys of E14.5 Grb2 conditional knockout (ureteric-bud specific) and wild-type embryos
2023-12-01 | GSE163040 | GEO
Project description:Context dependent molecular cues shape the formation of the cerebral vascular network and the function of the blood-brain barrier (BBB). The Wnt/ß-catenin pathway is orchestrating CNS vascular development, but downstream mediators have not been characterized. Here we generated an endothelial cell-specific R26-Axin1 overexpression (AOE) mouse model to inhibit Wnt/ß-catenin signaling. In AOE mice we discovered that blockade of Wnt/ß-catenin pathway leads to premature regression and remodeling without compromising BBB integrity. Importantly, by comparing transcriptomes of endothelial cells from wildtype and AOE mice, we identified ADAMTSL2 as a novel Wnt/ß-catenin-induced, secreted factor, important for stabilizing the BBB during development. Zebrafish loss-of-function and gain-of-function models, further demonstrated that ADAMTSL2 is crucial for normal vascular development and could rescue vascular phenotypes in AOE zebrafish brains. In conclusion, the studies presented here reveal a hitherto unrecognized role of ADAMTSL2 as an endothelial cell-specific mediator of Wnt/ß-catenin signaling during CNS vascular development and BBB-formation.
2019-02-22 | GSE66848 | GEO
Project description:Hematopoietic stem cells (HSCs) are characterized by their ability to give rise to all mature blood lineages and to renew themselves. Despite their potential for the therapeutic use in cell replacement therapy, the cell fate decisions of HSCs controlled by extrinsic and intrinsic mechanisms remain poorly understood. In summary, our results provide a number of novel and important observations illustrating and enlightening the importance of ß-catenin in hematopoiesis. Specifically, we show that ß-catenin plays an essential role in the immortalization of HSCs. Keywords: hematopoietic stem cells , immortalization, ß-catenin, genetic modification, time course
2006-12-06 | GSE6424 | GEO
Project description:Ureteric bud (UB) is the embryonic kidney progenitor tissue that gives rise to the collecting duct and lower urinary tract. UB-like structures generated from human pluripotent stem cells by previously reported methods show limited developmental ability and limited branching. Here we report a new method to generate UB organoids that possess epithelial polarity and tubular lumen and repeat branching morphogenesis. We also succeeded in monitoring UB tip cells by utilizing the ability of tip cells to uptake very-low-density lipoprotein, cryopreserving UB progenitor cells and expanding UB tip cells that can reconstitute the organoids and differentiate into collecting duct progenitors. Moreover, we successfully reproduced some phenotypes of multicystic dysplastic kidney (MCDK) using the UB organoids. These methods will help elucidate the developmental mechanisms of UB branching and develop a selective differentiation method for collecting duct cells, contributing to the creation of disease models for congenital renal abnormalities.
2020-06-16 | GSE152471 | GEO
Project description:Ureteric bud (UB) is the embryonic kidney progenitor tissue that gives rise to the collecting duct and lower urinary tract. UB-like structures generated from human pluripotent stem cells by previously reported methods show limited developmental ability and limited branching. Here we report a new method to generate UB organoids that possess epithelial polarity and tubular lumen and repeat branching morphogenesis. We also succeeded in monitoring UB tip cells by utilizing the ability of tip cells to uptake very-low-density lipoprotein, cryopreserving UB progenitor cells and expanding UB tip cells that can reconstitute the organoids and differentiate into collecting duct progenitors. Moreover, we successfully reproduced some phenotypes of multicystic dysplastic kidney (MCDK) using the UB organoids. These methods will help elucidate the developmental mechanisms of UB branching and develop a selective differentiation method for collecting duct cells, contributing to the creation of disease models for congenital renal abnormalities.
2020-06-16 | GSE152470 | GEO
Project description:The Wnt/ß-catenin pathway is orchestrating the development of the blood-brain barrier (BBB), but its downstream mediators have remained elusive. To identify potential effectors, we generated an endothelial cell specific Axin1 over-expressing mouse model, AOEiEC. We found that in AOEiE mice Wnt/ß-catenin signalling was down regulated leading to premature regression and remodelling without directly compromising BBB integrity. Interestingly, by comparing transcriptomes of endothelial cells from control and AOEiEC mice, we identified Adamtsl2 as a novel Wnt/ß-catenin-induced, secreted factor, important for stabilizing the cerebral vasculature during development. Importantly, loss-of-function and gain-of-function experiments revealed that Adamtsl2 alone was sufficient to rescue CNS vascular defects seen upon Wnt-signalling inhibition. Furthermore, using various cell and animal models we demonstrate that Adamtsl2 exerts its function by fine-tuning the TGFβ signalling pathway in CNS vessels. In conclusion, this study implicates Adamtsl2 as a mediator of Wnt/ß-catenin signalling during BBB development by linking it to TGFβ signalling.
2019-01-31 | GSE77874 | GEO
Project description:Focal nodular hyperplasias (FNHs) are benign liver lesions considered to be a hyperplastic response to increased blood flow in otherwise normal liver. In contrast, FNH-like nodules occur in cirrhotic liver but share similar histopathological features. To better understand the pathophysiology of FNH, we performed a transcriptomic analysis. Methods: Affymetrix and cDNA microarrays were used to compare gene expression in eight FNHs with that in tissue from six normal livers. Selected genes were validated with quantitative RT-PCR in 70 benign liver tumors including adenomas and cirrhotic and FNH-like lesions. Results: Among the deregulated genes in FNHs, 19 were physiologically zonated in the normal liver lobule. All six periveinous genes were up-regulated in FNH, whereas 13 genes normally expressed in the periportal area were down-regulated. Immunohistochemistry revealed that glutamine synthetase was markedly overexpressed, forming anastomosed areas usually centered on visible veins. ß-catenin mRNA was slightly but significantly overexpressed, as were several known ß-catenin target genes. Moreover, activated hypophosphorylated ß-catenin protein accumulated in FNH in the absence of activating mutations. These results suggest zonated activation of the ß-catenin pathway specifically in FNH, whereas the other benign hepatocellular tumors, including FNH-like lesions, demonstrated an entirely different pattern of ß-catenin expression. Conclusions: In FNH, increased expression of the ß-catenin pathway was restricted to enlarged periveinous areas, which may explain the slight polyclonal over-proliferation of hepatocytes at the origin of the lesion. FNH-like nodules may have a different pathogenetic origin. Keywords: Disease state analysis
2008-06-18 | GSE9536 | GEO
Project description:GDNF signaling through the Ret receptor tyrosine kinase is critical for ureteric bud branching morphogenesis during kidney development yet few of the downstream genes are currently known. We find that the ETS transcription factors Etv4 and Etv5 are positively regulated by Ret signaling in ureteric bud tips. Etv4-/-Etv5+/- mice display either renal agenesis or severe hypodysplasia, while kidney development fails completely in double homozygotes. We identify several genes whose expression in the ureteric bud depends on Etv4 and Etv5, including Cxcr4, Myb, Met, Mmp14. Thus, Etv4 and Etv5 are key components of a gene network downstream of Ret that promotes and controls renal branching morphogenesis. Experiment Overall Design: 3 plus GDNF and 2 minus GDNF chips were analyzed with different pooled samples for each chip (U74Av2 and 430A). Sample comparisons and statistical analysis were performed using dChip 1.3, using the Comparison Analysis feature to identify genes differentially expressed between the two groups. The following filtering criteria were used: the “lower limit” for fold-change between the means of the +GDNF and -GDNF samples must exceed 1.2 with a 90% confidence limit, and the absolute difference between the two group means must exceed 100.
2009-10-02 | E-GEOD-18267 | biostudies-arrayexpress
Project description:HCT116 colorectal cancer cells were treated with a novel inhibitor of ß-catenin/BCL9 interaction and evaluated for transcriptional changes using RNA-seq.
2022-01-01 | GSE182086 | GEO