October 2012
Volume 53, Issue 11
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Research Highlight  |   October 2012
Existence of the Canonical Wnt Signaling Pathway in the Human Trabecular Meshwork
Investigative Ophthalmology & Visual Science October 2012, Vol.53, 6972. doi:10.1167/iovs.12-10985
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      Jose M. Gonzalez; Existence of the Canonical Wnt Signaling Pathway in the Human Trabecular Meshwork. Invest. Ophthalmol. Vis. Sci. 2012;53(11):6972. doi: 10.1167/iovs.12-10985.

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      © ARVO (1962-2015); The Authors (2016-present)

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Mao et al. 1 have discovered a potential contributor to the etiology of POAG and a new target for glaucoma pharmacotherapy. The authors have provided strong evidence for the presence of a canonical Wnt signaling pathway in the human trabecular meshwork that can regulate IOP. They were able to show that when cultured human trabecular meshwork (HTM) cells were treated with Wnt3a, an activating ligand of the Wnt signaling pathway, (1) β-catenin was translocated to the nucleus, (2) cells induced gene expression through TCF/LEF cis-elements, and (3) endogenous expression of AXIN2 was upregulated. AXIN2 is a Wnt signaling–related gene with TCF/LEF regulatory elements in its promoter region. These effects were blocked by cotreatment with a Wnt signaling inhibitor, secreted frizzled-related protein 1 (sFRP1). 
The authors ruled out a role for noncanonical Wnt signaling pathways, particularly the planar cell polarity (PCP)-Rho-Rho kinase (ROCK) pathway, using both cell culture and live mouse studies. Mice overexpressing either sFRP1 or DKK1 had significantly elevated IOP compared with sham controls (by over 60%). Dickkopf-1 (DKK1) blocks the interaction between Wnt and a coreceptor, low density lipoprotein receptor-related protein 5 and 6 (LRP5/6). The PCP-Rho-ROCK pathway does not require LRP5/6. Moreover, the PCP-Rho-ROCK pathway can alter the actin cytoskeleton. Wnt3a treatment of HTM cells had no effect on the distribution of filamentous actin or the phosphorylation of myosin light chain kinase, a marker of actin-driven contractility. 
Ruling out the noncanonical PCP-Rho-ROCK pathway makes this report especially significant because ROCK and contractility have already been established as important regulators of IOP. The canonical Wnt signaling pathway represents a new avenue of discovery that could yield new insights into the origin of glaucoma as well as new therapies. For example, ocular hypertension induced by sFRP1 was partially suppressed by a small molecule glycogen synthase kinase-3 beta (GSK3β) inhibitor. 2 The mechanism of IOP elevation due to inhibited Wnt signaling is unknown and needs to be elucidated. One possible line of inquiry is the role of cell-cell junctions, especially those mediated by cadherins. 3,4  
References
Mao W Millar JC Wang WH Existence of the canonical Wnt signaling pathway in the human trabecular meshwork. Invest Ophthalmol Vis Sci . 2012;53:7043–7051. [CrossRef] [PubMed]
Wang WH McNatt LG Pang IH Increased expression of the WNT antagonist sFRP-1 in glaucoma elevates intraocular pressure. J Clin Invest . 2008;118:1056–1064. [PubMed]
Bill A Lütjen-Drecoll E Svedbergh B. Effects of intracameral Na2EDTA and EGTA on aqueous outflow routes in the monkey eye. Invest Ophthalmol Vis Sci . 1980;19:492–504. [PubMed]
Gonzalez JM Jr Faralli JA Peters JM Newman JR Peters DM. Effect of heparin II domain of fibronectin on actin cytoskeleton and adherens junctions in human trabecular meshwork cells. Invest Ophthalmol Vis Sci . 2006;47:2924–2931. [CrossRef] [PubMed]
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