Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Regulation of Mouse Lens Development and Gene Expression by KrÃ¼ppel-Like Factor 4

ABSTRACT: Conditional disruption of Klf4 in the ectoderm-derived tissues of the eye results in defective cornea, conjunctiva and the lens. Expression of Klf4 is first detected in the embryonic day-12 (E12) mouse lens, peaks at E16, and declines thereafter. Lenses from Mice which were conditional null for Klf4 (Klf4CN) were characterized by morphology and transcriptome. Wild type and Klf4-conditional null mouse lens gene expression at embryonic day 16.5 (E16.5) and postnatal day 56 (PN56) was surveyed using Affymetrix mouse whole genome 430 2 arrays.

ORGANISM(S): Mus musculus

SUBMITTER: Stephen Harvey

PROVIDER: E-GEOD-47694 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Regulation of mouse lens maturation and gene expression by Krüppel-like factor 4.

Gupta Divya D Gupta Divya D Harvey Stephen A K SA Kenchegowda Doreswamy D Swamynathan Sudha S Swamynathan Shivalingappa K SK

Experimental eye research 20130925

Conditional disruption of Klf4 in the surface ectoderm-derived tissues of the eye results in defective cornea, conjunctiva and the lens. This report describes the effects of disruption of Klf4 in the lens in greater detail. Expression of Klf4, first detected in the embryonic day-12 (E12) mouse lens, peaked at E16 and was decreased in later stages. Early embryonic disruption of Klf4 resulted in a smaller lens with cortical vacuolation and nuclear opacity. Microarray comparison of Klf4CN and WT le ...[more]

PMID: 24076321

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Project description:The mature eye lens contains a surface layer of epithelial cells called the lens epithelium that require a functional mitochondrial population to maintain the homeostasis and transparency of the entire lens. The lens epithelium overlies a core of terminally differentiated fiber cells that must degrade their mitochondria to achieve lens transparency. These distinct mitochondrial populations make the lens a useful model system to identify those genes that regulate the balance between mitochondrial homeostasis and elimination. Here we used an RNA sequencing and bioinformatics approach to identify the transcript levels of all genes expressed by distinct regions of the lens epithelium and maturing fiber cells of the embryonic Gallus gallus (chicken) lens. Our analysis detected over 15,000 unique transcripts expressed by the embryonic chicken lens. Of these, over 3000 transcripts exhibited significant differences in expression between lens epithelial cells and fiber cells. Multiple transcripts coding for separate mitochondrial homeostatic and degradation mechanisms were identified to exhibit preferred patterns of expression in lens epithelial cells that require mitochondria relative to lens fiber cells that require mitochondrial elimination. These included differences in the expression levels of metabolic, autophagy, and mitophagy transcripts between lens epithelial cells and lens fiber cells. These data provide a comprehensive window into all genes transcribed by the lens and those mitochondrial regulatory and degradation pathways that function to maintain mitochondrial populations in the lens epithelium and to eliminate mitochondria in maturing lens fiber cells. Differentiation-state transcriptional analysis of embryonic chicken lenses was performed following microdissection of 100 embryonic day 13 (E13) chicken lenses into four distinct regions that represent a continuum of lens cell differentiation states: lens central epithelium (EC), equatorial epithelium (EQ), cortical fibers (FP), and central fibers (FC). Further analysis of the transcriptional content of biologically replicate samples was performed by Illumina directional mRNA sequencing and resulting reads mapped by TopHat and assembled with Cufflinks.

Project description:Background: FGF signaling controls numerous processes during cell lineage specification, organogenesis and terminal differentiation. In lens, FGF signaling was implicated as the key pathway that controls lens fiber cell differentiation, but little is known about its full range and spectrum of regulated genes. Results: Herein, we employed rat lens epithelial explant system and performed RNA and microRNA expression profiling in cells induced to differentiate by FGF2. The primary data were collected at explants grown overnight in the presence of 5 ng/ml of FGF2, followed by a treatment with 100 ng/ml of FGF2 and collection of samples at 2, 4, 12 and 24 hours. Global analysis identified extensive FGF2-regulated cellular responses that were both independent and dependent on microRNAs (miRNAs). We identified a total number of 131 FGF2-regulated miRNAs. Forty-four of these microRNAs had at least two predicted and inversely regulated target RNA molecules. The genes regulated by the highest number of miRs include Nfib, Nfat5, c-Maf, Ets1 and N-Myc, all encoding DNA-binding transcription factors. Analysis of RNA data revealed that activated FGF signaling influenced other major signaling pathways known to regulate lens differentiation including BMP/TGF-M-NM-2, Notch, and Wnt signaling. In the M-bM-^@M-^\earlyM-bM-^@M-^] response phase (2-4 hours), miRNAs targeted expression of batteries of genes that control transcription, cell death, cell proliferation, cell junction, and protein serine/threonine kinase activity. In M-bM-^@M-^\lateM-bM-^@M-^] stages (12-24 hours), the main miRNA targets included regulators of cell cycle arrest and cellular differentiation. Specific miRNA:mRNA interaction networks were identified for c-Maf, N-Myc, and Nfib (DNA-binding transcription factors); Cnot6, Dicer1, Fbx33 and Wdr47 (RNA processing); Ash1l, Med1/PBP and Kdm5b (chromatin remodeling); and c-Maf, Ets1 and Stc1 (FGF signaling). MicroRNAs including miR-9, -143, -155, -455 and -543 downregulated expression of c-Maf in the 3M-bM-^@M-^Y-UTR luciferase reporter asssays. The functional requirement for miRNAs in lens was further demonstrated via disrupted lens fiber cell differentiation in lenses with inactivated Dicer1. Conclusions: These studies demonstrate for the first time global impact of activated FGF signaling in lens cell culture system and identified novel gene regulatory networks (GRNs) connected by multiple miRNAs. Differential gene expression of FGF2-treated lens cell cultures was analyzed at 0, 2, 4, 12 and 24 hours following the treatment. Two biological replicate experiments were performed.

Dataset Information

Regulation of Mouse Lens Development and Gene Expression by KrÃ¼ppel-Like Factor 4

Publications

Regulation of mouse lens maturation and gene expression by Krüppel-like factor 4.

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