Tissue-specific Regulation of the Mouse αA-crystallin Gene in Lens via Recruitment of Pax6 and c-Maf to its Promoter

Yang, Ying; Cvekl, Aleš

doi:10.1016/j.jmb.2005.05.072

Cited by 54 publications

(71 citation statements)

References 62 publications

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“…Transgenic studies to characterize temporal and spatial expression patterns directed from both −366/+46 (Govindarajan and Overbeek, 2001;Stolen and Griep, 2000) and −1800/+46 αA-crystallin promoter fragments found expression only in primary lens fibers that was at least 300-times lower than that of the endogenous αA-crystallin gene. Pax6 activates the -366/+46 promoter in co-transfections and multiple Pax6 binding sites were identified in the lens-specific promoter of the mouse αA-crystallin gene (Yang and Cvekl, 2005) as shown in Fig. 11.…”

Section: Transcriptional Control Of Lens Structural Genesmentioning

confidence: 96%

“…Regulation of the mouse αA-crystallin gene-Analysis of the temporal and spatial regulation of the mouse αA-crystallin gene provides a number of details that are not currently available for other crystallin genes. Three distinct DNA-binding transcription factors, Pax6, c-Maf, and CREB, were implicated as αA-crystallin regulatory factors (Ashery-Padan et al, 2000;Cvekl et al, 1995a;Kawauchi et al, 1999;Ring et al, 2000;Yang and Cvekl, 2005). Chromatin immunoprecipitations (ChIPs) of the mouse αA-crystallin locus confirmed the association of these factors with four regulatory regions of this gene and provided novel mechanistic insights into the regulation of αA-crystallin during lens fiber cell differentiation .…”

Section: Transcriptional Control Of Lens Structural Genesmentioning

confidence: 98%

“…Deletion of the bZIP protein, c-Maf, results in a lack of primary fiber cell elongation and a 99% reduction of αA-crystallin expression levels (Kawauchi et al, 1999;Ring et al, 2000). Like Pax6, c-Maf interacts with multiple regions of the αA-crystallin promoter and can activate its expression in co-transfection tests (Yang and Cvekl, 2005).…”

Section: Transcriptional Control Of Lens Structural Genesmentioning

confidence: 99%

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Genetic and epigenetic mechanisms of gene regulation during lens development

Cvekl

Duncan

2007

Progress in Retinal and Eye Research

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Recent studies demonstrated a number of links between chromatin structure, gene expression, extracellular signaling and cellular differentiation during lens development. Lens progenitor cells originate from a pool of common progenitor cells, the pre-placodal region (PPR) which is formed due to a complex exchange of extracellular signals between the neural plate, naïve ectoderm and mesendoderm. A specific commitment to the lens program over alternate choices such as the formation of olfactory epithelium or the anterior pituitary is manifested by the formation of a thickened surface ectoderm, the lens placode. Mouse lens progenitor cells are characterized by the expression of a complement of lens lineage-specific transcription factors including Pax6, Six3 and Sox2, controlled by FGF and BMP signaling, followed later by c-Maf, Mab21like1, Prox1 and FoxE3. Proliferation of lens progenitors together with their morphogenetic movements results in the formation of the lens vesicle. This transient structure, comprised of lens precursor cells, is polarized with its anterior cells retaining their epithelial morphology and proliferative capacity, whereas the posterior lens precursor cells initiate terminal differentiation forming the primary lens fibers. Lens differentiation is marked by expression and accumulation of crystallins and other structural proteins. The transcriptional control of crystallin genes is characterized by the reiterative use of transcription factors required for the establishment of lens precursors in combination with more ubiquitously expressed factors (e.g. AP-1, AP-2α, CREB and USF) and recruitment of histone acetyltransferases (HATs) CBP and p300, and chromatin remodeling complexes SWI/SNF and ISWI. These studies have poised the study of lens development at the forefront of efforts to understand the connections between development, cell signaling, gene transcription and chromatin remodeling.

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Section: Transcriptional Control Of Lens Structural Genesmentioning

confidence: 96%

Section: Transcriptional Control Of Lens Structural Genesmentioning

confidence: 98%

Section: Transcriptional Control Of Lens Structural Genesmentioning

confidence: 99%

See 1 more Smart Citation

Genetic and epigenetic mechanisms of gene regulation during lens development

Cvekl

Duncan

2007

Progress in Retinal and Eye Research

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141

124

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“…Pax6 and Hsf4 cDNAs were obtained in the CMV vectors pKW10 and pCMV6-XL6, respectively (Yang et al 2006;OriGene). Transient co-transfections were conducted in mouse lens epithelial αTN4 cells (Yang and Cvekl, 2005). The cells were transfected using Lipofectamine 2000 (Life Technologies) with 0.5 µg firefly luciferase reporter plasmid, 200 ng empty control vector ( pKW10/pCMV6-XL6) or expression plasmids.…”

Section: Transient Transfections and Reporter Gene Analysismentioning

confidence: 99%

Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation

Limi

McGreal

et al. 2016

Development

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Ocular lens morphogenesis is a model for investigating mechanisms of cellular differentiation, spatial and temporal gene expression control, and chromatin regulation. Brg1 (Smarca4) and Snf2h (Smarca5) are catalytic subunits of distinct ATP-dependent chromatin remodeling complexes implicated in transcriptional regulation. Previous studies have shown that Brg1 regulates both lens fiber cell differentiation and organized degradation of their nuclei (denucleation). Here, we employed a conditional Snf2h flox mouse model to probe the cellular and molecular mechanisms of lens formation. Depletion of Snf2h induces premature and expanded differentiation of lens precursor cells forming the lens vesicle, implicating Snf2h as a key regulator of lens vesicle polarity through spatial control of Prox1, Jag1, p27Kip1 (Cdkn1b) and p57Kip2 (Cdkn1c) gene expression. The abnormal Snf2h −/− fiber cells also retain their nuclei. RNA profiling of Snf2h −/− and Brg1 −/− eyes revealed differences in multiple transcripts, including prominent downregulation of those encoding Hsf4 and DNase IIβ, which are implicated in the denucleation process. In summary, our data suggest that Snf2h is essential for the establishment of lens vesicle polarity, partitioning of prospective lens epithelial and fiber cell compartments, lens fiber cell differentiation, and lens fiber cell nuclear degradation.

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“…The αA-crystallin (Cryaa) promoter has been shown to bind and to be activated by Pax6 in vitro (Cvekl et al, 1995;Yang and Cvekl, 2005;Yang et al, 2006). Accordingly, Pax6 was found to be required in vivo for the onset of Cryaa expression during early stages of lens development (Ashery-Padan et al, 2000;Cvekl et al, 1995).…”

Section: Pax6 Is Not Required For the Regulation Of Crystallin Genes mentioning

confidence: 99%

Pax6 is essential for lens fiber cell differentiation

et al. 2009

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The developing ocular lens provides an excellent model system with which to study the intrinsic and extrinsic cues governing cell differentiation. Although the transcription factors Pax6 and Sox2 have been shown to be essential for lens induction, their later roles during lens fiber differentiation remain largely unknown. Using Cre/loxP mutagenesis, we somatically inactivated Pax6 and Sox2 in the developing mouse lens during differentiation of the secondary lens fibers and explored the regulatory interactions of these two intrinsic factors with the canonical Wnt pathway. Analysis of the Pax6-deficient lenses revealed a requirement for Pax6 in cell cycle exit and differentiation into lens fiber cells. In addition, Pax6 disruption led to apoptosis of lens epithelial cells. We show that Pax6 regulates the Wnt antagonist Sfrp2 in the lens, and that Sox2 expression is upregulated in the Pax6-deficient lenses. However, our study demonstrates that the failure of differentiation following loss of Pax6 is independent of β-catenin signaling or Sox2 activity. This study reveals that Pax6 is pivotal for initiation of the lens fiber differentiation program in the mammalian eye.KEY WORDS: Pax6, Sox2, Lens, Crystallin, Wnt, β-catenin, Mouse Development 136, 2567Development 136, -2578Development 136, (2009 2568Chen et al., 2004;Chen et al., 2006). When the Wnt coreceptor Lrp6 was deleted in mice, aberrant LFCs appeared in the anterior pole of the lens (Stump et al., 2003). Upon inactivation of the canonical Wnt effector β-catenin, LE markers, proliferation and differentiation were disrupted (Cain et al., 2008). These findings suggest a role for Wnt signaling in LE cell fate.Owing to the severe ocular phenotype of Pax6 mutants, the later developmental roles of Pax6 could only be extrapolated from in vitro research. Herein, we introduce the first in vivo loss-of-function model of Pax6 and its presumed transcriptional partner Sox2. We show that the loss of Pax6 prevents LFC differentiation and results in cell death and in an increase in Sox2. However, conditional deletion of Sox2 reveals that it is dispensable for LFC differentiation. Furthermore, overexpression of β-catenin results in a differentiation failure that is similar to, but independent of, that observed following Pax6 loss. These findings place Pax6 upstream in the cascade of events leading to the differentiation of LE into lens fibers in mammals. MATERIALS AND METHODS Mouse linesMouse lines employed in this study were: Pax6 lox (Ashery-Padan et al., 2000), Mlr10 (Zhao et al., 2004), Catnb lox(ex3) (Harada et al., 1999) and BATlacZ (Nakaya et al., 2005) and are described in Fig. S1 in the supplementary material. The Sox2 loxP line (see Fig. 7A) contains two loxP sites inserted around the single exon of the murine Sox2 gene using conventional gene-targeting methods (Joyner, 1995). In the gene-targeting vector, loxP-frt-pMC1neopA-frt, the neo gene is flanked by frt sites. Flp recombinase activity within the B6.SJL-Tg(ACTFLPe)9205Dym/J mouse line (Rodriguez et al.,...

show abstract

Tissue-specific Regulation of the Mouse αA-crystallin Gene in Lens via Recruitment of Pax6 and c-Maf to its Promoter

Cited by 54 publications

References 62 publications

Genetic and epigenetic mechanisms of gene regulation during lens development

Genetic and epigenetic mechanisms of gene regulation during lens development

Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation

Pax6 is essential for lens fiber cell differentiation

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