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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Expression data from E12.5 embryonic kidneys isolated from wild-type and Ret-deficient mice

ABSTRACT: To better understand the signaling and transcriptional events involved in the GDNF-independent emergence of the ureteric bud from the Wolffian duct, microarray expression analysis was performed on embryonic kidneys from wild-type and Ret-deficient mice. Microarray data was used to identify genes and gene networks involved in the GDNF-independent outgrowth of the ureteric bud. Whole embryonic kidneys from E12.5 Ret mutant and wild-type mice were isolated. Isolated kidneys were lysed and RNA was extracted with the Qiagen RNEasy Micro kit. The RNA was amplified using the NuGEn Ovation kit and hybridized to the Affymetrix GeneChip Mouse Whole Genome 430 2.0 microarray. Three biological replicates for Ret-knockout and wild-type kidneys were performed.

ORGANISM(S): Mus musculus

SUBMITTER: Sanjay Nigam

PROVIDER: E-GEOD-32093 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data from E12.5 embryonic kidneys isolated from wild-type and Ret-deficient mice

Project description:To better understand the signaling and transcriptional events involved in the GDNF-independent emergence of the ureteric bud from the Wolffian duct, microarray expression analysis was performed on embryonic kidneys from wild-type and Ret-deficient mice. Microarray data was used to identify genes and gene networks involved in the GDNF-independent outgrowth of the ureteric bud.

2012-04-01 | GSE32093 | GEO

Transcription profiling of mouse knockouts for Etv4 and Etv5 - plusGDNF and minusGDNF comparison using U74Av2 and 430A arrays

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

HNF1B controls epithelial organization and cell polarity during ureteric bud branching and collecting duct morphogenesis

Project description:Kidney development depends critically on proper ureteric bud branching giving rise to the entire collecting duct system. The transcription factor HNF1B is required for the early steps of ureteric bud branching. Yet, the molecular and cellular events regulated by HNF1B are poorly understood. We report that specific removal of Hnf1b from the ureteric bud leads to defective cell-cell contacts and apico-basal polarity during the early branching events. High resolution ex vivo imaging combined with a membranous fluorescent reporter strategy show decreased mutant cell-rearrangements during mitosis-associated cell dispersal and severe epithelial disorganisation. Molecular analysis reveals downregulation of Gdnf-Ret pathway components and suggests that HNF1B acts both upstream and downstream of Ret-signaling by directly regulating Gfrα1 and Etv5. Subsequently, Hnf1b-deletion leads to massively mispatterned ureteric tree network, defective collecting duct differentiation and disrupted tissue architecture leading to cystogenesis. Consistently, mRNA-seq analysis performed from E15.5 control and mutant kidneys shows that the most impacted genes encode intrinsic cell-membrane components with transporter activity. Our study uncovers a fundamental and recurrring role of HNF1B in epithelial organization during early ureteric bud branching and further patterning and differentiation of the collecting duct system. Article submitted to Development. Authors: Audrey Desgrange, Claire Heliot,Ilya Skovorodkin, Saad U. Akram, Janne Heikkilä, Veli-Pekka Ronkainen, Ilkka Miinalainen I., Seppo J. Vainio and Silvia Cereghini

2017-12-15 | GSE106085 | GEO

GDNF-RET signaling as a target in aromatase inhibitor resistant breast cancers

Project description:Understanding the complex molecular mechanisms underlying resistance to endocrine therapy is a major challenge in the treatment of estrogen receptor-positive (ER+) breast cancers. We have previously demonstrated that glial cell line-derived neurotrophic factor (GDNF) signaling via the receptor tyrosine kinase RET promotes estrogen independent activation of ER. Here we have addressed the relevance of GDNF-RET signaling in response to aromatase inhibitor treatment and explored the efficacy of using RET inhibitors in breast cancer models of aromatase inhibitor response and resistance. A GDNF-response gene set, identified from gene expression profiling, was demonstrated to be an independent prognostic marker of poor patient outcome and, importantly, to be predictive of poor response to aromatase inhibitor treatment and development of resistance. The relevance of these findings was validated first by demonstrating an association of RET protein expression in an independent cohort of aromatase inhibitor resistant patient samples. Second, in in vitro models, GDNF-mediated RET signaling was demonstrated to enhance the survival of aromatase inhibitor resistant cells and to increase resistance in aromatase inhibitor sensitive cells. These effects could be reversed by targeting GDNF/RET signaling with the RET selective inhibitor NVP-BBT594 thus identifying GDNF-RET signaling as a potential therapeutic target, particularly in breast cancers resistant to aromatase inhibitors.<br>MCF7 cells were E2-deprived by culturing in phenol red-free RPMI 1640 supplemented with 10% DCC for 3 days and then serum-starved overnight in the presence or absence of fulvestrant (ICI182,780) (100 nM). The following day, cells were treated with GDNF (20 ng/ml) for 0, 4, 8, 24 and 48 hours in the presence or absence of fulvestrant (ICI182,780) (100 nM).

2013-01-17 | E-MEXP-3662 | biostudies-arrayexpress

RET Ligands Mediate Endocrine Sensitivity via a Bi-stable Feedback Loop with ERα

Project description:The molecular mechanisms of endocrine resistance in breast cancer remain poorly understood. Here we used PRO-seq to map the location of hundreds of genes and thousands of distal enhancers whose activities differ between endocrine sensitive and resistant MCF-7 cells. Our genome-wide screen identified a 16-fold transcriptional increase in glial-cell line derived neurotrophic factor (GDNF), a RET tyrosine kinase receptor ligand, which is both necessary and sufficient for resistance in MCF-7 cells. GDNF causes endocrine resistance by switching the active state of a bi-stable feedback loop from ERα signaling to GDNF-RET signaling. To catalyze this switch, we found that GDNF directly downregulates ERα transcription and activates the transcription factor EGR1, which, in turn, induces GDNF expression. Remarkably, both MCF-7 cells and ER+ primary tumors appear poised for endocrine resistance via the RET signaling pathway, but lack robust RET ligand expression and only develop resistance upon expression of GDNF or other RET ligands.

2018-02-22 | GSE93229 | GEO

Comparison of E14.5 embryonic kidney transcriptomes (Grb2 ureteric-specific knockout vs wild-type)

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

Mouse embryonic kidneys (E13.5): mutant (UB HDAC1,2-/-) vs. wild type

Project description:Transcriptional profiling of mouse embryonic kidneys (E13.5) comparing UB HDAC1,2-/- kidneys with wild type kidneys. Studies in our lab showed that histone deacetylase 1 (HDAC1) and 2 (HDAC2) perform redundant, yet essential functions in the developing mouse ureteric bud (UB) tissue. Double deletion of HDAC1 and HDAC2 in the UB results in impaired UB branching morphogenesis, followed by severe kidney dysgenesis. The goal of the microarray analysis was to identify the genetic pathways controlled by HDAC1 and 2 in the UB.

2012-01-31 | GSE35432 | GEO

Mouse embryonic kidneys (E13.5): mutant (UB HDAC1,2-/-) vs. wild type

2012-01-31 | E-GEOD-35432 | biostudies-arrayexpress

Whole kidneys at embryonic day 14.5: wildtype (WT) versus Hoxb7Cre transgene mediated conditional Mdm4 knockout kidneys

Project description:Transcriptional profiling of mouse embryonic kidneys lacking Mdm4 function in the ureteric bud lineage

2020-06-01 | GSE137994 | GEO

Stabilization of ß-catenin during murine Kidney Development

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

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