Abstract
The Wnt/β-catenin signaling pathway controls many processes during development, including cell proliferation, cell differentiation and tissue homeostasis, and its aberrant regulation has been linked to various pathologies. In this study we investigated the effect of ectopic activation of Wnt/β-catenin signaling during lens fiber cell differentiation. To activate Wnt/β-catenin signaling in lens fiber cells, the transgenic mouse referred to as αA-CLEF was generated, in which the transactivation domain of β-catenin was fused to the DNA-binding protein LEF1, and expression of the transgene was controlled by αA-crystallin promoter. Constitutive activation of Wnt/β-catenin signaling in lens fiber cells of αA-CLEF mice resulted in abnormal and delayed fiber cell differentiation. Moreover, adult αA-CLEF mice developed cataract, microphthalmia and manifested downregulated levels of γ-crystallins in lenses. We provide evidence of aberrant expression of cell cycle regulators in embryonic lenses of αA-CLEF transgenic mice resulting in the delay in cell cycle exit and in the shift of fiber cell differentiation to the central fiber cell compartment. Our results indicate that precise regulation of the Wnt/β-catenin signaling activity during later stages of lens development is essential for proper lens fiber cell differentiation and lens transparency.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cataract / genetics*
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Cataract / metabolism
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Cell Cycle / genetics
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Cell Differentiation / genetics*
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Crystallins / genetics
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Crystallins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Epithelial Cells / metabolism
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Gene Expression Regulation, Developmental
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Humans
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Lens, Crystalline / metabolism
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Lymphoid Enhancer-Binding Factor 1
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic / genetics
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Mice, Transgenic / metabolism
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Microphthalmos / genetics
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Microphthalmos / metabolism
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Promoter Regions, Genetic / genetics
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Signal Transduction / genetics
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Wnt Signaling Pathway / genetics*
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beta Catenin / genetics*
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beta Catenin / metabolism
Substances
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Crystallins
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DNA-Binding Proteins
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Lef1 protein, mouse
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Lymphoid Enhancer-Binding Factor 1
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beta Catenin
Grants and funding
This study was supported by the Grant Agency of the Czech Republic (P305/11/2198 and P305/12/2042), Grant Agency of Charles University in Prague (GAUK 243-253051),by Czech Ministry of Education (LK11214), by OP EC CZ 1.07/2.3.00/30.0027 "Founding the Centre of Transgenic Technologies" (Operational Program Education for Competitiveness by Ministry of Education, Youth and Sports, Czech Republic+European Social Fund), and by IMG institutional support RVO68378050. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.