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Yi Zhou, Christopher P Tanzie, Ting Xie; N-cadherin-mediated cell adhesion regulates epithelium polarity and morphogenesis in the developing ciliary body of the mouse eye. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4461.
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Glaucoma is one of the leading causes of irreversible blindness worldwide and is often associated with elevated intraocular pressure (IOP). The ciliary body (CB), a bilayered epithelial structure with underlying stroma, is involved in regulating IOP and hence often serves as the pharmacologic target for glaucoma. Despite the significant role it plays in ocular health and homeostasis, its development and morphogenesis remains poorly understood. Previously, we determined that Notch2 regulates CB morphogenesis at least in part by regulating cell proliferation and BMP signaling. Here we show that cell adhesion mediated by N-cadherin regulates cell polarity and morphogenesis independently of Notch2 and BMP signaling.
We used Trp1-cre mediated loxp recombination to selectively knock-out N-cadherin in both CB epithelial layers. Mutants and littermate controls were harvested at multiple developmental stages for analysis. Standard procedures including immunohistochemistry, in-situ hybridization, BrdU labeling, TUNEL staining and Western blotting were performed to characterize the mutant phenotype. To further support our hypothesis, we used the human RPE cell line ARPE19 to knock-down N-cadherin by shRNA and measured the changes of polarity caused by the reduction of N-cadherin.
N-cadherin mutants display about 50% penetrance with regards to defective CB morphogenesis. Immunostaining results show that N-cadherin depletion affects neither Notch2 nor BMP signaling. BrdU labeling results indicate that N-cadherin is required to maintain high levels of cellular proliferation. Interestingly, localization of the apical polarity marker Par3 is compromised in N-cadherin mutants, and its proper localization correlates well with the degree of morphogenesis, suggesting that N-cadherin might regulate morphogenesis, at least in part, through regulation of cell polarity.
Our previous study demonstrated that Notch2 regulates CB morphogenesis. These results identify the important role of N-cadherin-mediated cell adhesion in regulating CB development. N-cadherin regulates CB morphogenesis by stabilizing Par3-based apical polarity. These findings expand our understanding of CB development and provide insight into the cross-talk of important signaling pathways, which may be applied in other systems as well.
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