Ectopic Activation of Wnt/beta-Catenin Signaling in Lens Fiber Cells Results in Cataract Formation and Aberrant Fiber Cell Differentiation
Abstract
The Wnt/beta-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/beta-catenin signaling during lens fiber cell differentiation.
To activate Wnt/beta-catenin signaling in lens fiber cells, the transgenic mouse referred to as alpha A-CLEF was generated, in which the transactivation domain of beta-catenin was fused to the DNA-binding protein LEF1, and expression of the transgene was controlled by alpha A-crystallin promoter. Constitutive activation of Wnt/beta-catenin signaling in lens fiber cells of alpha A-CLEF mice resulted in abnormal and delayed fiber cell differentiation.
Moreover, adult alpha A-CLEF mice developed cataract, microphthalmia and manifested downregulated levels of gamma-crystallins in lenses. We provide evidence of aberrant expression of cell cycle regulators in embryonic lenses of alpha A-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/beta-catenin signaling activity during later stages of lens development is essential for proper lens fiber cell differentiation and lens transparency.