Antagonistic action of Six3 and Prox1 at the gamma-crystallin promoter

Lengler, Johannes; Krausz, Eberhard; Tomarev, Stanislav I.; Prescott, Alan R.; Quinlan, Roy A.; Graw, Jochen

doi:10.1093/nar/29.2.515

Cited by 60 publications

(44 citation statements)

References 49 publications

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“…2 Reciprocally, phosphorylated ERK is expressed throughout the proliferative population of epithelial cells in neonatal rat lens, extending into the transitional zone (28). Although it is known that several transcriptional factors such as Pax6, Sox2, and Six3 also regulate the expression of crystallin gene (13,34,35), L-Maf is the first example of a differentiation factor that can be regulated directly by FGF signaling in lens development.…”

Section: Discussionmentioning

confidence: 99%

The Stability of the Lens-specific Maf Protein is Regulated by Fibroblast Growth Factor (FGF)/ERK Signaling in Lens Fiber Differentiation

Ochi

Ogino²,

Kageyama

et al. 2003

Journal of Biological Chemistry

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Fibroblast growth factor (FGF) signaling is necessary for both proliferation and differentiation of lens cells. However, the molecular mechanisms by which FGFs exert their effects on the lens remain poorly understood. In this study, we show that FGF-2 repressed the expression of lens-specific genes at the proliferative phase in primary cultured lens cells. Using transfected cells, we also found that the activity of L-Maf, a lens differentiation factor, is repressed by FGF/ERK signaling. L-Maf is shown to be phosphorylated by ERK, and introduction of mutations into the ERK target sites on L-Maf promotes its stabilization. The stable L-Maf mutant protein promotes the differentiation of lens cells from neural retina cells. Taken together, these results indicate that FGF/ERK signaling negatively regulates the function of L-Maf in proliferative lens cells and that stabilization of the L-Maf protein is important for lens fiber differentiation.The vertebrate lens consists of only two cell populations, and because of this simple tissue organization, it provides an excellent model of cell differentiation. The anterior surface of the lens is covered by a simple epithelium, whereas the remainder and bulk of the lens is composed of elongated lens fibers (1). During embryonic development and throughout the life of the organism, fiber cells are added via differentiation of the lens epithelial cells. The proliferative epithelial cells in the anterior germinative zone move across the lens equator to the posterior transitional zone followed by withdrawal of cell cycling and differentiation into fiber cells. Fiber cell differentiation is characterized by cell elongation and the eventual degradation of all cellular organelles including the nucleus. (7), and a secreted form of FGFR can cause a delay in fiber differentiation (9). Together, these studies implicate FGFs as bifunctional molecules that regulate both proliferation and differentiation of the lens cells. The transcription factors that mediate FGF signaling in lens development and the molecular mechanisms used by FGFs to regulate the transcriptional factors remain to be identified. Several transcription factors, including Pax6, Sox2, Six3, c-Maf, and L-Maf, are known to be important in lens development and in regulating the expression of lens-specific genes such as crystallin genes (10 -17). Of these factors, L-Maf is one of the most attractive candidates for mediating FGF signaling, because L-Maf has been identified as a lens-specific regulator of avian ␣A-crystallin expression (14), and c-maf-deficient mice have defective lens fiber differentiation and loss of crystallin gene expression (16, 17). There results show that Mafs are critical for expression of crystallin genes and lens fiber differentiation. L-Maf is a basic region/leucine zipper transcription factor and regulates the expression of ␣A-crystallin by binding the lens-specific enhancer element ␣CE2 (14, 18). In chicken, the expression of L-maf is initiated in the lens placode and is subsequently restricted to th...

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Section: Discussionmentioning

confidence: 99%

The Stability of the Lens-specific Maf Protein is Regulated by Fibroblast Growth Factor (FGF)/ERK Signaling in Lens Fiber Differentiation

Ochi

Ogino²,

Kageyama

et al. 2003

Journal of Biological Chemistry

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“…Prox1 Activates the Chicken ␤B1-Crystallin Promoter-The vertebrate homolog of Drosophila Prospero, Prox1, is crucial for lens fiber cell elongation (14) and is able to activate ␥-crystallin promoters in transfection assays (16). To test whether Prox1 is also capable of activating the chicken ␤B1-crystallin promoter, co-transfection assays were performed with a Prox1 expression vector in N/N 1003A cells.…”

Section: Pl1 and Pl2 Elements Are Essential For Chicken ␤B1-crys-mentioning

confidence: 99%

“…Prox1 null lenses do not undergo lens fiber cell elongation, although the expression of several fiber cell-specific genes can be detected by RT-PCR (14). In co-transfection assays, Prox1 activates several ␥-crystallin promoters (16). However, it has not been established whether Prox1 is a DNA binding transcription factor like its Drosophila homolog, Prospero (17,18).…”

mentioning

confidence: 99%

Mafs, Prox1, and Pax6 Can Regulate Chicken βB1-Crystallin Gene Expression

Cui

Tomarev

Piatigorsky

et al. 2004

Journal of Biological Chemistry

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During lens fiber cell differentiation, the regulation of crystallin gene expression is coupled with dramatic morphological changes. Here we report that Mafs, Prox1, and Pax6, which are essential transcription factors for normal lens development, bind to three functionally important cis elements, PL1, PL2, and OL2, in the chicken ␤B1-crystallin promoter and may cooperatively direct the transcription of this lens fiber cell preferred gene. Gel shift assays demonstrated that Mafs bind to the MARE-like sequences in the PL1 and PL2 elements, whereas Prox1, a sequence-specific DNA-binding protein like its Drosophila homolog Prospero, interacts with the OL2 element. Furthermore, Pax6, a known repressor of the chicken ␤B1-crystallin promoter, binds to all three of these cis elements. In transfection assays, Mafs and Prox1 activated the chicken ␤B1-crystallin promoter; however, their transactivation ability was repressed when co-transfected with Pax6. Taken together with the known spatiotemporal expression patterns of Mafs, Prox1, and Pax6 in the developing lens, we propose that Pax6 occupies and represses the chicken ␤B1-crystallin promoter in lens epithelial cells, and is displaced by Prox1 and Mafs, which activate the promoter, in differentiating cortical fiber cells.

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“…Although misexpression of Six3 in the medaka converts otic vesicles into lens cells, as evidenced by the expression of crystallin-expressing lens-like structures (Oliver et al, 1996), similar results have not been reported in any other species to date. In mice, Six3 has been found to repress γ-crystallin promoter activity when assayed in N/N1003A and CD5A cells (Lengler et al, 2001). A recent report demonstrates that gain of Six3 function in lens primordium by in ovo electroporation of chick embryos causes an arrest of lens placode invagination and suppresses lens fiber differentiation (Zhu et al, 2002).…”

Section: Six3 In Placode Formationmentioning

confidence: 99%

“…Using cell lines, Prox1 was shown to activate γ-crystallin expression through the responsive element located between nt-151 and nt-174 of the gene promoter (Lengler et al, 2001), suggesting that Prox1 may exert some regulatory effects on later expressed crystallins, including β-crystallin, in the chick.…”

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confidence: 99%

Lens differentiation and crystallin regulation: a chick model

Reza¹,

Yasuda²

2004

Int. J. Dev. Biol.

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The vertebrate lens is a transparent polarized tissue that acts as the gateway for vision. The chick lens is an excellent model for studying tissue organogenesis, since it is both accessible and easily manipulated during embryonic stages. The chick lens consists of two morphologically discrete compartments, the epithelium and the fiber-cell mass. Evidence indicates that the early phases of lens development involve several sequential events, including tissue interactions, cell proliferation and differentiation. The morphological change during lens development is associated with the concurrent and distinct functions of numerous transcription factors. Diffusible molecules from the complementary neural tissue play vital roles during the entire process of lens development. Lens tissue is characterized by the ample production of crystallins, lens specific proteins which provide structural integrity and functional properties to the lens. Thus, the study of crystallin regulation should provide insight into the development of a functional lens during embryogenesis. This process has been shown to involve a complex and evolutionary conserved pathway supported by different regulatory proteins.

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Antagonistic action of Six3 and Prox1 at the gamma-crystallin promoter

Cited by 60 publications

References 49 publications

The Stability of the Lens-specific Maf Protein is Regulated by Fibroblast Growth Factor (FGF)/ERK Signaling in Lens Fiber Differentiation

The Stability of the Lens-specific Maf Protein is Regulated by Fibroblast Growth Factor (FGF)/ERK Signaling in Lens Fiber Differentiation

Mafs, Prox1, and Pax6 Can Regulate Chicken βB1-Crystallin Gene Expression

Lens differentiation and crystallin regulation: a chick model

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