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Laser capture-microarray analysis of Lim1 mutant kidney development.

ABSTRACT: The Lim1 gene has essential functions during several stages of kidney development. In particular, a tissue specific knockout in the early metanephric mesenchyme results in the formation of the earliest nephron precursor, the renal vesicle, but failure of this structure to progress to the next stage, the comma shaped body. To better understand the molecular nature of this developmental arrest we used a laser capture microdissection-microarray strategy to examine the perturbed gene expression pattern of the mutant renal vesicles. Among the genes found differently expressed were Chrdl2, an inhibitor of BMP signaling, the pro-apoptotic factor Bmf, as well as myob5, an atypical myosin which modulates chemokine and transferring signaling, and pdgfr1, which is important in epithelial folding. Of particular interest, the microarray data indicated that the Dkk1 gene, which encodes an inhibitor of Wnt signaling, was downregulated nine fold in mutants. This was confirmed by in situ hybridizations. It is interesting to note that Lim1 and Dkk1 mutant mice have striking similarities in phenotype. These results suggest that the Dkk1 gene might be a key downstream effector of Lim1 function. Keywords: Lim1 mutant, kidney development, gene expression profile comparison

ORGANISM(S): Mus musculus

PROVIDER: GSE7257 | GEO | 2007/04/10

SECONDARY ACCESSION(S): PRJNA98013

REPOSITORIES: GEO

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Transcription profiling of mouse wild type and Lim1-null renal vesicles microdissected from embryonic day 12.5 kidneys

Project description:The Lim1 gene has essential functions during several stages of kidney development. In particular, a tissue specific knockout in the early metanephric mesenchyme results in the formation of the earliest nephron precursor, the renal vesicle, but failure of this structure to progress to the next stage, the comma shaped body. To better understand the molecular nature of this developmental arrest we used a laser capture microdissection-microarray strategy to examine the perturbed gene expression pattern of the mutant renal vesicles. Among the genes found differently expressed were Chrdl2, an inhibitor of BMP signaling, the pro-apoptotic factor Bmf, as well as myob5, an atypical myosin which modulates chemokine and transferring signaling, and pdgfr1, which is important in epithelial folding. Of particular interest, the microarray data indicated that the Dkk1 gene, which encodes an inhibitor of Wnt signaling, was downregulated nine fold in mutants. This was confirmed by in situ hybridizations. It is interesting to note that Lim1 and Dkk1 mutant mice have striking similarities in phenotype. These results suggest that the Dkk1 gene might be a key downstream effector of Lim1 function. Experiment Overall Design: We compared gene expression profiles of wild type and mutant Lim1 renal vesicles, which were isolated from E12.5 kidneys by laser capture microdissection. Nine biological independent samples were examined, with four mutant and five wild type. Each sample included approximately 30-50 renal vesicles. Detailed protocols are described at GUDMAP.org

2007-12-12 | E-GEOD-7257 | biostudies-arrayexpress

Gene expression profiles in developing nephrons using Lim1 metanephric mesenchyme-specific conditional mutant mice

Project description:BACKGROUND: Lim1 is a homeobox gene that is essential for nephrogenesis. During metanephric kidney development, Lim1 is expressed in the nephric duct, ureteric buds, and the induced metanephric mesenchyme. Conditional ablation of Lim1 in the metanephric mesenchyme blocks the formation of nephrons at the nephric vesicle stage, leading to the production of small, non-functional kidneys that lack nephrons. METHODS: In the present study, we used Affymetrix probe arrays to screen for nephron-specific genes by comparing the expression profiles of control and Lim1 conditional mutant kidneys. Kidneys from two developmental stages, embryonic day 14.5 (E14.5) and 18.5 (E18.5), were examined. RESULTS: Comparison of E18.5 kidney expression profiles generated a list of 465 nephron-specific gene candidates that showed a more than 2-fold increase in their expression level in control kidney versus the Lim1 conditional mutant kidney. Computational analysis confirmed that this screen enriched for kidney-specific genes. Furthermore, at least twenty-eight of the top fifty (56%) candidates (or their vertebrate orthologs) were previously reported to have a nephron-specific expression pattern. Our analysis of E14.5 expression data yielded 41 candidate genes that are up-regulated in the control kidneys compared to the conditional mutants. Three of them are related to the Notch signaling pathway that is known to be important in cell fate determination and nephron patterning. CONCLUSIONS: Therefore, we demonstrate that Lim1 conditional mutant kidneys serve as a novel tissue source for comprehensive expression studies and provide a means to identify nephron-specific genes. Keywords: tissue specificity, time course, development, kidney, metanephric mesenchyme, nephron, Lim1, knockout mice, conditional knockout

2006-02-13 | GSE4230 | GEO

Mus musculus

Project description:Laser capture-microarray analysis of Lim1 mutant kidney development.

| PRJNA98013 | ENA

Transcription factor LIM1 progresses tumor growth in endometrial cancer via CREB signaling.

Project description:The incidence of endometrial cancer (EC) is increasing worldwide, however, therapeutic options for EC are limited and novel therapeutic targets for EC are required. We reanalyzed RNA-seq data of EC registered in The Cancer Genome Atlas and found significant upregulation of transcription factor LIM homeobox1 (LIM1) in stages II-IV compared to stage I of EC patients. LIM1-knocked down (LIM1-KD) and Control sublines were established using HEC50B cell line and then RNA-sequence results were analyzed by Ingenuity pathway analysis (IPA). It revealed enrichment of CREB signaling-related genes among differentially expressed genes between Control and LIM1-KD sublines. Also, decreased levels of phosphorylated CREB were observed in LIM1-KD subline. In the Xenograft model used by HEC50B sublines, tumor growth was significantly suppressed in the LIM1-KD subline compared to Control subline. Immunofluorescent staining showed decreased phosphorylation of CREB in LIM1-KD-derived tumors. Kaplan-Meier plotter analysis indicated that the high LIM1 expression group had a significantly poorer prognosis. These results suggest that LIM1 in EC progresses tumor growth and malignancy via CREB signaling.

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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

Stabilization of ß-catenin during murine Kidney Development

2011-03-28 | GSE20325 | GEO

A Parathyroid Hormone/Salt Inducible Kinase Signaling Axis Controls Renal Vitamin D Activation and Organismal Calcium Homeostasis [SK]

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Molecular Basis of Renal Adaptation in a Murine Model of Congenital Obstructive Nephropathy

Project description:Congenital obstructive nephropathy is a common cause of chronic kidney disease and a leading indication for renal transplant in children. The cellular and molecular responses of the kidney to congenital obstruction are incompletely characterized. In this study, we evaluated global transcription in kidneys with graded hydronephrosis in the megabladder (mgb-/-) mouse to better understand the pathophysiology of congenital obstructive nephropathy. Three primary pathways associated with kidney remodeling/repair were induced in mgb-/- kidneys independent of the degree of hydronephrosis. These pathways included retinoid signaling, steroid hormone metabolism, and renal response to injury. Urothelial proliferation and the expression of genes with roles in the integrity and maintenance of the renal urothelium were selectively increased in mgb-/- kidneys. Ngal/Lcn2, a marker of acute kidney injury, was elevated in 36% of kidneys with higher grades of hydronephrosis. Evaluation of Ngalhigh versus Ngallow kidneys identified the expression of several novel candidate markers of renal injury. This study indicates that the development of progressive hydronephrosis in mgb-/- mice results in renal adaptation that includes significant changes in the morphology and potential functionality of the renal urothelium. These observations will permit the development of novel biomarkers and therapeutic approaches to progressive renal injury in the context of congenital obstruction. Gene expression was measured in control, mild, moderate and severely hydronephrotic megabladder mouse kidneys. A total of 6 control kidneys were compared to 18 mutant kidneys from age-matched male animals.

2013-06-18 | E-GEOD-48041 | biostudies-arrayexpress

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