CTNND1 variants cause familial exudative vitreoretinopathy through the Wnt/cadherin axis
Mu Yang, Shujin Li, Li Huang, Rulian Zhao, Erkuan Dai, Xiaoyan Jiang, Yunqi He, Jinglin Lu, Li Peng, Wenjing Liu, Zhaotian Zhang, Dan Jiang, Yi Zhang, Zhilin Jiang, Yeming Yang, Peiquan Zhao, Xianjun Zhu, Xiaoyan Ding, Zhenglin Yang
Mu Yang, Shujin Li, Li Huang, Rulian Zhao, Erkuan Dai, Xiaoyan Jiang, Yunqi He, Jinglin Lu, Li Peng, Wenjing Liu, Zhaotian Zhang, Dan Jiang, Yi Zhang, Zhilin Jiang, Yeming Yang, Peiquan Zhao, Xianjun Zhu, Xiaoyan Ding, Zhenglin Yang
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Research Article Genetics Ophthalmology

CTNND1 variants cause familial exudative vitreoretinopathy through the Wnt/cadherin axis

Abstract

Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder that can cause vision loss. CTNND1 encodes a cellular adhesion protein p120-catenin (p120), which is essential for vascularization with unclear function in postnatal physiological angiogenesis. Here, we applied whole-exome sequencing to 140 probands of FEVR families and identified 3 candidate variants in the human CTNND1 gene. We performed inducible deletion of Ctnnd1 in the postnatal mouse endothelial cells (ECs) and observed typical phenotypes of FEVR with reactive gliosis. Using unbiased proteomics analysis combined with experimental approaches, we conclude that p120 is critical for the integrity of adherens junctions (AJs) and that p120 activates Wnt signaling activity by protecting β-catenin from glycogen synthase kinase 3 beta–ubiqutin–guided (Gsk3β-ubiquitin–guided) degradation. Treatment of CTNND1-depleted human retinal microvascular ECs with Gsk3β inhibitors LiCl or CHIR-99021 enhanced cell proliferation. Moreover, LiCl treatment increased vessel density in Ctnnd1-deficient mouse retinas. Variants in CTNND1 caused FEVR by compromising the expression of AJs and Wnt signaling activity. Genetic interactions between p120 and β-catenin or α-catenin revealed by double-heterozygous deletion in mice showed that p120 regulates vascular development through the Wnt/cadherin axis. In conclusion, variants in CTNND1 can cause FEVR through the Wnt/cadherin axis.

Authors

Mu Yang, Shujin Li, Li Huang, Rulian Zhao, Erkuan Dai, Xiaoyan Jiang, Yunqi He, Jinglin Lu, Li Peng, Wenjing Liu, Zhaotian Zhang, Dan Jiang, Yi Zhang, Zhilin Jiang, Yeming Yang, Peiquan Zhao, Xianjun Zhu, Xiaoyan Ding, Zhenglin Yang

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Figure 10

FEVR-like phenotypes in double-heterozygous deletion of Ctnnd1 and Ctnna1 or Ctnnb1 in mouse ECs and schematic diagram of the mechanism for p120 deficiency in the pathogenesis of FEVR.

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FEVR-like phenotypes in double-heterozygous deletion of Ctnnd1 and Ctnna...
(A) Representative immunofluorescence images of P5 Ctrl, Ctnnd1iECKO/+, and Ctnnd1iECKO/+ Ctnnb1iECKO/+ mouse retinas labeled with IB4 (green) and Ter119 (red). The white arrows indicate abnormal leakage of erythrocytes. Scale bars, 200 μm. (B) Representative immunofluorescence images of P7 Ctrl, Ctnnd1iECKO/+, and Ctnnd1iECKO/+ Ctnna1iECKO/+ mouse retinas labeled with IB4 (green) and Ter119 (red). The white arrows and dotted region indicate abnormal leakage of erythrocytes. Scale bars, 200 μm. (C) Quantification of vascular progression of P5 Ctrl, Ctnnd1iECKO/+, and Ctnnd1iECKO/+ Ctnnb1iECKO/+ mouse retinas. Error bars, SDs. The P values are from multiple comparisons in 1-way ANOVA with Dunnett’s multiple comparisons tests (n = 6); ****P < 0.0001. (D) Quantification of vascular progression of P7 Ctrl, Ctnnd1iECKO/+, and Ctnnd1iECKO/+ Ctnna1iECKO/+ mouse retinas. Error bars, SDs. The P values are from multiple comparisons in 1-way ANOVA with Dunnett’s multiple comparisons tests (n = 6); ***P < 0.001. (E) Inactivation of Wnt signaling (upper panel) and disruption of AJs (lower panel) lead to similar but distinct retinal vascular defects. Deficient p120 function causes FEVR through combined effects of Wnt inactivation and AJ disruption (right panel). Inactivation of Wnt signaling contributes to i) delayed vascular progression, ii) decreased inner vessel density, iii) artery/vein intersection, iv) hyperplasia of peripheral vasculature, and v) moderate vascular leakage (upper panel). Disruption of AJs contributes to i) extensive vascular leakage and ii) vascular hyperplasia (lower panel). Experiments were performed at least 3 times independently.