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Wnt Activation by Wild Type and Mutant Myocilin in Cultured Human Trabecular Meshwork Cells

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Title: Wnt Activation by Wild Type and Mutant Myocilin in Cultured Human Trabecular Meshwork Cells
Author(s): Shen, Xiang; Ying, Hongyu; Yue, Beatrice Y. J. T.
Abstract: Background: Myocilin is a gene linked to the most prevalent form of glaucoma, a major blinding disease. The trabecular meshwork (TM), a specialized eye tissue, is believed to be involved, at least in part, in the development of glaucoma. The Pro370 to Leu (P370L) mutation of myocilin is associated with severe glaucoma phenotypes and Gln368 stop (Q368X) is the most common myocilin mutation reported. Myocilin, upon overexpression, has been shown to induce phenotypes that include a loss of actin stress fibers, an increase in the cAMP level and protein kinase A (PKA) activity, as well as a reduction in the RhoA activity. We examined herein whether Wnt signaling pathway is involved in the myocilin phenotypes and whether P370L and Q368X mutants also display biological effects similar to those of the wild type myocilin. Methodology/Principal Findings: Wild type myocilin, when transfected into cultured human TM cells, induced a loss of actin stress fibers as judged by phalloidin staining. Such a loss was averted by treatment of secreted Frizzled-related protein 1 (sFRP1), an inhibitor of Wnt signaling. Consistent with the notion that Wnt pathway mediates the myocilin phenotype, Wnt activation was demonstrated by TOP/FOP-Flash reporter assays. Treatment of human TM cells of a Wnt activator, SB216763, as well as transfection of myocilin P370L and Q368X mutants all resulted in actin stress fiber loss, PKA activation and RhoA inactivation. The PKA elevation was obviated by the sFRP1 treatment, indicating that Wnt signaling was upstream that of PKA. Conclusions/Significance: The present study demonstrated that following forced expression of wild type myocilin, Wnt was activated, triggering in turn other myocilin-related alterations. P370L and Q368X mutations induced similar phenotypes, suggesting one possible mechanism how the mutants may lead to TM cell damage and pathology.
Issue Date: 2012-09
Publisher: Public Library of Science
Citation Info: Shen X, Ying H, Yue BYJT (2012) Wnt Activation by Wild Type and Mutant Myocilin in Cultured Human Trabecular Meshwork Cells. PLoS ONE 7(9): e44902. doi:10.1371/journal.pone.0044902
Type: Article
Description: The original version is available through Public Library of Science at DOI: 10.1371/journal.pone.0044902. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
ISSN: 1932-6203
Sponsor: The work was supported by grants EY018828 and EY005628, and core grant EY001792 from the National Eye Institute
Date Available in INDIGO: 2013-11-26

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