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 8

Treatment with LiCl or CHIR-99021 corrects the Wnt signaling activity in CTNND1-KD HRECs and the vascular density of Ctnnd1iECKO/iECKO mouse retinas.

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Treatment with LiCl or CHIR-99021 corrects the Wnt signaling activity in...
(A) Western blot analysis of protein levels of β-catenin, VE-cadherin, c-Myc, and CyclinD1 in Ctrl and CTNND1-KD HRECs treated with LiCl, CHIR-99021, or vehicle. (B–E) Quantification of relative protein levels of β-catenin, VE-cadherin, c-Myc, and CyclinD1 in Ctrl and CTNND1-KD HRECs treated with LiCl, CHIR-99021, or vehicle. Error bars, SDs. The P values are from multiple comparisons in 1-way ANOVA with Dunnett’s or Tukey’s multiple comparisons test (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. (F) Representative immunofluorescence images of IB4-labeled (green) and Ter119-labeled (red) retina flat mounts from P7 Ctnnd1iECKO/iECKO mice treated with LiCl or NaCl. Scale bars, 200 μm. (G and H) Quantification of vascular density of remodeling plexus (G) and vascular progression (H) in P7 Ctnnd1iECKO/iECKO mouse retinas treated with LiCl or NaCl. Error bars, SDs. Student’s t test (n = 6), ****P < 0.0001. Experiments were performed at least 3 times independently.