An Essential Role for E-Cadherin in Maintenance of the Lens Epithelial Phenotype

Abstract

Purpose:: Cell adhesion molecules are thought to play important roles in multiple aspects of lens development. E-cadherin, possesses a distinct expression pattern within the developing lens, where it is more broadly localized to lens epithelial and elongating primary fibre cells during early embryonic development and maintained in lens epithelial cells during late embryogenesis, through to adulthood. Although its role in the lens is not well understood, E-cadherin expression has been shown to be an essential feature of epithelial cells.

Methods:: To more critically analyze the requirement for E-cadherin in lens morphogenesis, a mouse lacking E-cadherin within the developing lens and surface ectoderm was created using the Cre-loxP approach. Resultant mutant progeny (Le-Cre⁺;Cdh1^KO/flox) were compared with wildtype littermates in order to detect any significant morphological or immunohistochemical differences.

Results:: Le-Cre⁺;Cdh1^KO/flox mice exhibited severe microphthalmia as compared to their wild-type littermates, in addition to an iris defect in which a distinct pupil was not observed. Histological examination of these mutant mice at P0 indicated the presence of a large number of vacuoles within the transitional zone of differentiating fibre cells. Furthermore, adult Le-Cre⁺;Cdh1^KO/flox mice failed to exhibit the presence of a distinct, cuboidal lens epithelial cell layer, which was correlated with a substantial up-regulation of α-smooth muscle actin expression. Lenses of Le-Cre⁺;Cdh1^KO/flox mice also exhibited alterations in the normal distribution of of zona occludens-1 (ZO-1), a marker for apical, tight junction formation, indicative of a disruption in normal lens epithelial cell polarity. In addition to lens defects, the adult mutant cornea also showed developmental abnormalities in normal epithelial stratification. Abnormal neovascularization was also observed in the corneal stroma.

Conclusions:: Lens epithelial cell adhesion appeared to be maintained in the Le-Cre⁺;Cdh1^KO/flox mutant mice during embryogenesis and early post-natal development, demonstrating that adhesive properties of these cells can be sustained in the absence of E-cadherin. This likely occurs due to the presence of other cadherin molecules, such as N-cadherin. However, adult mutant lenses showed significant phenotypic changes and loss in cell polarity, demonstrating a specific role for E-cadherin in maintenance of the adult lens epithelial cell phenotype.

Keywords: development • cell adhesions/cell junctions • differentiation