title: Ectopic activation of Wnt/β-catenin signaling in lens fiber cells results in cataract formation and aberrant fiber cell differentiation.
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.
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic ; Department of Genetics and Microbiology, Faculty of Science, Charles University in Prague, Prague, Czech Republic.
authors.forename: Barbora
authors.initials: B
authors.lastname: Antosova
authors.forename: Jana
authors.initials: J
authors.lastname: Smolikova
authors.forename: Romana
authors.initials: R
authors.lastname: Borkovcova
authors.forename: Hynek
authors.initials: H
authors.lastname: Strnad
authors.forename: Jitka
authors.initials: J
authors.lastname: Lachova
authors.forename: Ondrej
authors.initials: O
authors.lastname: Machon
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Kozmik
mesh_terms: D000818:Animals; D002386:Cataract / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D003459:Crystallins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007908:Lens, Crystalline / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics / Q000378:metabolism; D008850:Microphthalmos / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D003459:Crystallins; D004268:DNA-Binding Proteins; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D051176:beta Catenin