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Yichen Wang, Yan Wang, Christopher D Riemann, Melinda K Duncan; Dysregulation of canonical Wnt signaling may result in aniridia fibrosis syndrome (AFS). Invest. Ophthalmol. Vis. Sci. 2017;58(8):2043.
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© ARVO (1962-2015); The Authors (2016-present)
Congenital aniridia (CI) is defined as iris hypoplasia at birth, and often results from PAX6 mutations/deletions. Surgical interventions for common CI sequelae such as cataract and glaucoma can lead to devastating fibrotic complications (AFS). While little is known about the pathogenesis of AFS, previous studies showed that Pax6 negatively regulates canonical Wnt signaling in the embryonic eye. As canonical Wnt and TGF-β signaling can synergize to drive fibrosis, this work tests the hypothesis that Pax6 haploinsufficiency leads to upregulated Wnt signaling in the adult eye, which upon surgically mediated TGF-β activation, results in AFS.
Penetrating corneal injury (PCI) was performed on Pax6+/- and Pax6+/+ mice to model post-surgery fibrotic responses. The expression of fibrotic, inflammatory, angiogenesis, proliferation and apoptotic markers was evaluated by confocal immunofluorescence (IF). Canonical Wnt reporter mice (TCF/Lef:H2B/GFP) were mated with Pax6+/- mice, then PCI performed on reporter carriers (R+). The activation of Wnt and TGF-β signaling was measured by the levels of β-catenin or TCF/GFP, and pSMAD3 respectively. Human AFS samples were obtained during surgical treatment of AFS and analyzed for marker expression as above.
Human AFS material is comprised of asmooth muscle actin (SMA), pSMAD3 and nuclear b-catenin positive myofibroblasts embeded in a fibrotic extracellular matrix. Unoperated adult Pax6+/- mice develop pockets of spontaneous lens epithelial cell (LEC) and corneal fibrosis . After surgery, Pax6+/- mice developed severe fibrosis at both the injury site and iris root associated with elevated levels of nuclear β-catenin and pSMAD3. Unoperated Pax6+/- R+ mice exhibit elevated canonical Wnt signaling compared to wildtype as measured by GFP expression. Upon surgery, TCF/GFP and pSMAD3 were co-localized in SMA expressing cells at the injury site. However, reporter positive Pax6+/- mice did not exhibit elevated fibrosis after injury which is likely consistent with the known effects of genetic background on the phenotype of the aniridic eye.
Pax6 haploinsufficiency results in a propensity to develop spontaneous ocular fibrosis. As these eyes also exhibit elevated TCF/Lef activity in the eye, this may synergize with elevated TGF-β signaling induced upon surgery to drive the pathogenesis of AFS.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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