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Gata3 directly regulates cell cycle exit-coupled lens fiber cell differentiation in mouse embryonic lens

ABSTRACT: Gata3 is a DNA-binding transcription factor involved in cellular differentiation in a variety of tissues. To investigate the role of Gata3 in lens development we conducted lens-specific conditional loss-of-function model of Gata3 and confirmed abnormal regulation of cell cycle exit-coupled lens differentiation and retention of nuclei in the mutated lens fibers. We analyzed transcriptomes between control and mutated lenses by RNA-seq and revealed dysregulation of genes encoding critical components of the lens differentiation cascade, including a subset of crystallin genes, down-regulation of Dnase2b and reduced expression of Cdkn1b/p27 and Cdkn1c/p57.

ORGANISM(S): Mus musculus

PROVIDER: GSE131291 | GEO | 2020/01/08

REPOSITORIES: GEO

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Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and their denucleation [lens tissue]

Project description:Genome-wide approach to identify the cell-autonomous role of Brg1 in lens fiber cell terminal differentiation. To examine roles of Brg1 in mouse lens development, a dnBrg1 transgenic construct was expressed using the lens-specific alphaA-crystallin promoter in postmitotic lens fiber cells. Morphological studies revealed abnormal lens fiber cell differentiation in transgenic lenses resulting in cataract. Electron microscopic studies showed abnormal lens suture formation and incomplete karyolysis (denucleation) of lens fiber cells. To identify genes regulated by Brg1, RNA expression profiling was performed in E15.5 embryonic wild type and dnBrg1 transgenic lenses. In addition, comparisons between differentially expressed genes in dnBrg1 transgenic, Pax6 heterozygous, and Hsf4 homozygous lenses identified multiple genes co-regulated by Brg1, Hsf4 and Pax6. Among them DNase IIbeta, a key enzyme required for lens fiber cell denucleation, was found downregulated in each of the Pax6, Brg1 and Hsf4 model systems. Lens-specific deletion of Brg1 using conditional gene targeting demonstrated that Brg1 was required for lens fiber cell differentiation and indirectly for retinal development but was not essential for lens lineage formation. Wild type and dnBrg1 transgenic lenses, 4 biological replicates each

2011-01-01 | E-GEOD-22322 | biostudies-arrayexpress

HSF4 microarray gene expression analysis in the newborn mouse lens.

Project description:Differential expression of HSF4 in null newborn mouse and wildtype lenses was examined to identify putative downstream targets of HSF4. To examine roles of Brg1 in mouse lens development, a dnBrg1 transgenic construct was expressed using the lens-specific aA-crystallin promoter in postmitotic lens fiber cells. Morphological studies revealed abnormal lens fiber cell differentiation in transgenic lenses resulting in cataract. Electron microscopic studies showed abnormal lens suture formation and incomplete karyolysis (denucleation) of lens fiber cells. To identify genes regulated by Brg1, RNA expression profiling was performed in E15.5 embryonic wild type and dnBrg1 transgenic lenses. In addition, comparisons between differentially expressed genes in dnBrg1 transgenic, Pax6 heterozygous, and Hsf4 homozygous lenses identified multiple genes co-regulated by Brg1, Hsf4 and Pax6. Among them DNase IIb, a key enzyme required for lens fiber cell denucleation, was found downregulated in each of the Pax6, Brg1 and Hsf4 model systems. Lens-specific deletion of Brg1 using conditional gene targeting demonstrated that Brg1 was required for lens fiber cell differentiation and indirectly for retinal development but was not essential for lens lineage formation. Keywords: Differential mRNA Expression Three biological replicate experiments were performed with HSF null and wildtype lenses.

2010-12-01 | E-GEOD-22362 | biostudies-arrayexpress

Chromatin remodeling enzyme Brg1 is required for mouse lens fiber cell terminal differentiation and their denucleation [lens tissue]

2011-01-01 | GSE22322 | GEO

HSF4 microarray gene expression analysis in the newborn mouse lens.

2010-12-01 | GSE22362 | GEO

Nuclear Organization of Lens Epithelium and Fiber Cells in Newborn Lens

Project description:Cellular differentiation is marked by temporally and spatially coordinated gene expression regulated at multiple levels within the nucleus. Sequence-specific DNA-binding transcription factor CTCF EDIT. Topologically associated domains (TADs). Using Hi-C, we investigated changes in chromatin organization between newborn (P0.5) mouse lens fiber and epithelium and compared them to embryonic stem (ES) cells. Compartments A and B. Using ChIP-seq, we determined localization of CTCF in both lens tissues Formation of lens-specific TADs is demonstrated via comparative studies of chromatin at Pax6, Prox1, Gata3, Hsf4, and crystallin loci (to be updated) between lens and ES cell nuclei. Our study has generated the first data on nuclear organization in lens epithelium and lens fibers and directly compared these data with ES cells.

2023-10-16 | GSE243851 | GEO

Project description:Age-related breakdown of lenticular crystallins is associated with lenticular disorders such as cataract. Despite playing a critical role in maintaining lens homeostasis, the mechanism(s) and consequences of this phenomenon are not well understood. Utilising a proteomic-based approach, this study characterised 238 endogenous peptides derived from age-related crystallin breakdowns present in the cortical tissues of young, middle-age and old human lenses. Quantitative mass spectrometry analysis showed that the concentration of a prominent crystallin breakdown product in the lens increased significantly with age, which, coupled with the age-related increase in variety of the LMW crystallin peptide in the lens cortex, suggests that a major crystallin breakdown event taking place in the human lens cortex shortly after middle-age. In-depth analysis on the crystallin peptide terminal amino acids indicate the presence of trypsin-like proteolysis in the lens cortical cells, providing useful information on the mechanism(s) that contribute to crystallin breakdown in the aging human lens. Taken together, this work enhances our understanding on the age-related crystallin breakdown process in the cortical tissues of the human lens.

2016-09-29 | PXD001630 | Pride

Murine lenses:βB2-crystallin W151C knock-in mice vs.wild type control mice

Project description:Transcriptional profiling of the lens in βB2-crystallin W151C mutation mice compared with wild type lenses

2023-02-21 | GSE225548 | GEO

Ectopic activation of Wnt/beta-catenin signaling in lens fiber cells results in cataract formation.

Project description:Transgenic mouse line called alphaA-CLEF in which transactivation domain of beta-catenin is fused to the amino terminus of DNA-binding protein LEF and the expression of transgenic protein is controlled by alphaA-crystallin promoter (-342/+49) was used to mimic the activation of canonical Wnt/beta-catenin signaling in lens fiber cells. The aim of this experiment was to compare the mRNA expression in wild type and transgenic (CLEF) P1-P3 lenses and reveal the differentially expressed genes.

2014-02-11 | E-MTAB-1691 | biostudies-arrayexpress

Change in translation efficiency in mouse eyes at P0.5 by RNG140 knockout

Project description:RNG140 is an RNA-binding protein that increases in expression during eye lens differentiation and is involved in lens formation. However, the relevance of RNG140-mediated translational regulation to differentiation is not well understood. RNG140-mediated translational regulation operates in the mouse eye, where RNG140 knockout increased the translation of long mRNAs. mRNAs involved in lens differentiation, such as crystallin mRNAs, are short, and can escape translational inhibition by RNG140 and be translated in differentiating lenses.

2020-07-31 | GSE141842 | GEO

Conditional ablation of the Notch2 receptor in the ocular lens

Project description:Notch signaling is essential for proper lens development, however the specific requirements of individual Notch receptors has not been previously investigated. Here we report the lens phenotypes of Notch2 conditionally mutant mice, which exhibited severe microphthalmia, reduced pupillary openings, disrupted fiber cell morphology, eventual loss of the anterior epithelium, fiber cell dysgenesis, and cataracts. Notch2 mutants also had a persistent lens stalk phenotype at E11.5, and aberrant DNA synthesis in the fiber cell compartment by E14.5. Gene expression analyses showed elevated levels of the cell cycle regulators Cdkn1a (p21Cip1), Ccnd2 (CyclinD2) and Trp63 (p63) that negatively regulates Wnt signaling. Although removal of Notch2 phenocopied the increased proportion of fiber cells of Rbpj and Jag1 conditional mutant lenses, Notch2 is not required for AEL proliferation, suggesting that a different receptor regulates this process. Instead, we found that the Notch2 normally blocks progenitor cell death. Overall, we conclude that Notch2-mediated signaling regulates lens morphogenesis, apoptosis, cell cycle withdrawal, and secondary fiber cell differentiation. We have compared gene expression of ocular lenses of mice that are lens specific conditional mutants of Notch2 gene to that of littermate controls that had no ablation of Notch2 gene in the lens. Two lenses of each of the three conditional mutants and controls were pooled together and total RNA was harvested from embryonic day 19.5 (E19.5) lenses. Gene expression changes caused by absence of Notch2 gene in the lens were analyzed.

2011-12-31 | E-GEOD-31643 | biostudies-arrayexpress

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