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Yichen Wang, Yan Wang, Christopher Riemann, Melinda K Duncan; Molecular Mechanisms of Aniridia Fibrosis Syndrome (AFS). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):897.
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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 sequala such as cataract, glaucoma, and keratopathy may be complicated by AFS which can lead to devastating fibrotic complications. While little is known about the pathogenesis of AFS, previous studies showed that Pax6 negatively regulates Wnt signaling, the chronic upregulation of which can drive fibrosis. Thus, this work tests the hypothesis that haploinsufficiency of Pax6 leads to the upregulation of Wnt signaling, which may contribute to a pro-fibrotic state, resulting in AFS following surgeries.
Immunofluorescence (IF) staining was used to characterize human AFS samples by detecting the expression of fibrotic markers. Penetrating central corneal wounding was performed in Pax6+/tm1Pgr and wildtype (WT) mice to study fibrotic responses at day 5/9 post-surgery, followed by IF staining to detect the expression of fibrotic markers. To study the signaling pathways, the activation state of Wnt and TGF-β signaling was measured by the levels of β-catenin and pSMAD3 respectively.
In human AFS samples, abundant cells expressing myofibroblast markers were found, confirming that AFS is a classic fibrotic disease. Further, both β-catenin and pSMAD3 was detected, indicating the activation of Wnt and TGF-β signaling. In unoperated Pax6+/tm1Pgr mice, elevated levels of β-catenin were observed in pockets of spontaneous fibrosis, suggesting the chronic elevation of Wnt signaling. After surgery, Pax6+/tm1Pgr mice displayed severe fibrosis at the injury site. They also developed distal fibrosis at the iris root, which was absent in WT mice. Higher levels of β-catenin and pSMAD3 were found in Pax6+/tm1Pgr mice at both the injury site and iris root compared to WT.
AFS is a classic fibrotic disease. Chronic upregulation of Wnt signaling was confirmed in unoperated Pax6+/tm1Pgr mice. Compared to WT, Pax6 mutant mice exhibited increased fibrosis along with higher levels of β-catenin and pSMAD3 post-surgery. These data suggest that Pax6 haploinsufficiency leads to a pro-fibrotic state in aniridic eyes due to elevated Wnt signaling, which may lead to AFS following surgery.
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