CTNND1 variants cause familial exudative vitreoretinopathy through the Wnt/cadherin axis
Mu Yang, … , Xiaoyan Ding, Zhenglin Yang
Mu Yang, … , Xiaoyan Ding, Zhenglin Yang
Published June 14, 2022
Citation Information: JCI Insight. 2022;7(14):e158428. https://doi.org/10.1172/jci.insight.158428.
View: Text | PDF
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

×

Figure 5

p120 mainly participates in cadherin and Wnt signaling in HRECs.

Options: View larger image (or click on image) Download as PowerPoint
p120 mainly participates in cadherin and Wnt signaling in HRECs. (A) Vol...
(A) Volcano plot of differentially expressed genes detected by unbiased proteomics in the CTNND1-KD HRECs compared to Ctrl HRECs. The P values (–log10 transformed) are displayed as a function of the log2-transformed fold changes. The dashed lines indicate the threshold of P < 0.05 and fold change > 1.5. The sorted downregulated and upregulated genes are shown as yellow and red dots, respectively; genes without significant alteration are shown as blue dots. (B) Pathway classification of differentially expressed proteins using the PANTHER classification system online, showing remarkable enrichment for cadherin and Wnt signaling pathways. (C) Western blot analysis of protein levels of cadherin/catenin components (p120, α-catenin, β-catenin, and VE-cadherin) in Ctrl and CTNND1-KD HRECs. (D–F) Quantification of relative α-catenin, β-catenin, and VE-cadherin protein levels in Ctrl and CTNND1-KD HRECs. Error bars, SDs. Student’s t test (n = 3), **P < 0.01, ***P < 0.001, ****P < 0.0001. (G–I) Quantification of relative CTNNA1, CTNNB1, and CDH5 mRNA levels detected by real-time quantitative PCR (RT-qPCR) in Ctrl and CTNND1-KD HRECs. Error bars, SDs. Student’s t test (n = 3). Experiments were performed at least 3 times independently.