Ocular Anterior Segment Dysgenesis upon Ablation of p120 Catenin in Neural Crest Cells

Abstract

PURPOSE. Development of the ocular anterior segment depends largely on periocular mesenchyme cells, which are derived predominantly from neural crest cells (NCC). Specific and differential cell adhesion is expected to be instrumental in induction, migration, and differentiation of NCC. As p120 catenin (ctn) is an important component of cadherin-catenin cell adhesion complexes, we assessed its role in development of the anterior segment structure. METHODS.We generated conditional p120ctn fl/fl ;Wnt1Cre knockout mice and studied the effect of this gene ablation on eye development in vivo. In addition, p120ctn was knocked down in vitro.RESULTS. Wnt1Cre-mediated deletion of floxed p120ctn alleles in NCC resulted in serious ocular anterior segment dysgenesis (ASD), including iridocorneal angle closure, complete anterior chamber obliteration, iris and ciliary body hypoplasia, corneal malformation and opacity, and glaucoma-like defects. A completely penetrant phenotype was visible approximately three weeks after birth, but histologic defects were obvious at embryonal day 18.5 (E18.5). Neither migration of NCC nor expression of key transcription factors appeared to be affected. In contrast, the N-cadherin expression pattern was changed significantly in iridocorneal angle cells and corneal endothelium. A human trabecular meshwork cell line in which p120ctn was knocked down also showed decreased expression levels of N-cadherin and b-catenin at the plasma membrane, but no defect in cell migration.CONCLUSIONS. p120ctn has a critical role in ocular mesenchyme development. Loss of p120ctn and the associated N-cadherin downregulation in NCC leads to ASD without affecting cell migration. p120ctn abnormalities might have a role in the pathophysiology of mammalian eye development. (Invest Ophthalmol Vis Sci. 2012;53:5139-5153)

p120-catenin-dependent junctional recruitment of Shroom3 is required for apical constriction during lens pit morphogenesis

“…4A, arrows), the lens pits pinched off in all embryos examined. However, one abnormality observed was the absence of the gap that is normally present between the lens vesicle and ocular mesenchyme, which is consistent with the findings of another study in which p120-catenin was depleted specifically in the ocular mesenchyme (Tian et al, 2012). Analysis of doubly heterozygous Shroom3 +/Gt ; p120 +/flox embryos revealed that, like Shroom3 Gt/Gt mutants, their lateral lens pit epithelia at stage II-III exhibit quantitatively less curvature, at later stages fail to develop hinge points, and at E15.5 the lens vesicle remains attached to the cornea (Fig.…”

“…A role for p120-catenin during early mouse eye morphogenesis is consistent with other investigations showing that loss of p120-catenin causes eye defects in both Drosophila and Xenopus (Ciesiolka et al, 2004;Larson et al, 2008). In addition, ocular mesenchymal deletion of p120-catenin leads to anterior segment abnormalities in mice (Tian et al, 2012). Although these defects are attributed to altered morphogenesis, it remains unclear exactly how the tissues are affected.…”

Loss of p120-Catenin Induces Metastatic Progression of Breast Cancer by Inducing Anoikis Resistance and Augmenting Growth Factor Receptor Signaling

“…Others and we have shown that genetic ablation of E-cadherin or p120 in mouse mammary epithelial cells results in the induction of apoptosis, indicating that inactivation of adherens junction function is not tolerated in the mammary gland (4,14,15). In contrast, genetic inactivation in other organ systems does not induce cell death, but instead induces impaired tissue homeostasis and hyperplasia (16)(17)(18)(19). Also, p120 inactivation in mice seems to result in inflammation, which may be caused by a loss of barrier function and the production of inflammatory chemoattractants (17,18,20).…”

Update on Anterior Segment Development with Emphasis on Genetics and Correlation with Pathogenesis of Developmental & Primary Open Angle Glaucoma

“…These last 2 findings where indicative of an induced glaucoma. The migration of neural crest cells however was not affected indicating an effect on differentiation [34].…”

“…Therefore the analysis of p120 ctn status in human ocular disorders might be justified in future studies [34]. The ocular phenotype of the TGFα transgenic mice mentioned before also has features in common with Peter's anomaly in humans, therefore the authors have exam-ined the expression pattern for the possible mutation of PAX6 in both TGFα trans-genic and non-transgenic eyes, but no differences in PAX6 expression were detected [15].…”