Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy

Shujin Li; Mu Yang; Rulian Zhao; Li Peng; Wenjing Liu; Xiaoyan Jiang; Yunqi He; Erkuan Dai; Lin Zhang; Yeming Yang; Yi Shi; Peiquan Zhao; Zhenglin Yang; Xianjun Zhu

doi:10.1016/j.gendis.2022.10.003

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Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy

Full-length article | 更新时间：2024-02-04

- Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy
- Genes & Diseases Vol. 1, Issue 6, Pages: 2572-2585(2023)
- 作者机构：
  
  1. The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China,Sichuan,Chengdu,China,610072
  2. Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital,Sichuan,Chengdu,China,610072
  3. Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,China,200092
  4. Key Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology,Qinghai,Xining,China,810008
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2022.10.003
  CLC：
- Published：2023，
  
  Published Online：1 November 2023，
扫描看全文
Shujin Li, Mu Yang, Rulian Zhao, et al. Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy. [J]. Genes & Diseases 1(6):2572-2585(2023)
DOI：

Shujin Li, Mu Yang, Rulian Zhao, et al. Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy. [J]. Genes & Diseases 1(6):2572-2585(2023) DOI： 10.1016/j.gendis.2022.10.003.

摘要

Abstract

Endoplasmic reticulum (ER) membrane protein complex (EMC) is required for the co-translational insertion of newly synthesized multi-transmembrane proteins. Compromised EMC function in different cell types has been implicated in multiple diseases. Using inducible genetic mouse models

we revealed defects in retinal vascularization upon endothelial cell (EC) specific deletion of

Emc1

the largest subunit of EMC. Loss of

Emc1

in ECs led to reduced vascular progression and vascular density

diminished tip cell sprouts

and vascular leakage. We then performed an unbiased transcriptomic analysis on human retinal microvascular endothelial cells (HRECs) and revealed a pivotal role of EMC1 in the β-catenin signaling pathway. Further

in-vitro

and

in-vivo

experiments proved that loss of EMC1 led to compromised β-catenin signaling activity through reduced expression of Wnt receptor FZD4

which could be restored by lithium chloride (LiCl) treatment. Driven by these findings

we screened genomic DNA samples from familial exudative vitreoretinopathy (FEVR) patients and identified one heterozygous variant in

EMC1

that co-segregated with FEVR phenotype in the family.

In-vitro

expression experiments revealed that this variant allele failed to facilitate the expression of FZD4 on the plasma membrane and activate the β-catenin signaling pathway

which might be a main cause of FEVR. In conclusion

our findings reveal that variants in

EMC1

gene cause compromised β-catenin signaling activity

which may be associated with the pathogenesis of FEVR.

关键词

Keywords

Angiogenesisβ-catenin signalingEMC1Familial exudative vitreoretinopathyLiCl

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