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.
Highlights
Mouse lens morphogenesis begins with the formation of a lens placode in the head surface ectoderm in response to inductive signals from several tissues including the underlying optic vesicle
Since aA-crystallin promoter is active from embryonic day 12.5 [34], we examined the transgene expression in eyes starting from developmental stage E11.5
Since active Wnt/b-catenin signaling is known to regulate the cell cycle [42], and as the persistence of fiber cell differentiation markers in the fiber cell compartment of transgenic aA-CLEF lenses suggested delayed differentiation of fiber cells, we examined the expression of cell cycle promoting factors cyclin D1, cyclin D2 and the expression of negative regulators of cell cycle p27Kip1 and p57Kip2 [43]
Summary
Mouse lens morphogenesis begins with the formation of a lens placode in the head surface ectoderm in response to inductive signals from several tissues including the underlying optic vesicle. It is not surprising that the Wnt/bcatenin signaling pathway has been implicated in the regulation of various stages of lens development [21,22,23,24,25,26], including lens fiber and epithelial cell differentiation [21,26,27]. B-catenin has a dual role in the cell: besides its critical role as a transcriptional coactivator of the Wnt/b-catenin signaling pathway, it functions as a structural protein on the cell membranes in cadherinmediated cell adhesion at adherens junctions [28] Both of these bcatenin functions, transcriptional and cytoskeletal, have been shown to play a critical role in proper lens development and differentiation [21,22,23,24,25,26]. That ectopic activation of Wnt/b-catenin signaling in lens fiber cells using a transgenic mouse model results in aberrant lens fiber cell differentiation and cataract formation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
