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The ER membrane protein complex subunit emc3 controls angiogenesis via the FZD4/WNT signaling axis

Science China(Life Sciences) 2021年第11期64卷 1868-1883页

作者： Mu Yang Shujin Li Wenjing Liu† Xiao Li Yunqi He Yeming Yang Kuanxiang Sun Lin Zhang Wanli Tian Lixin Duan Huafu Chen Dezhong Yao Zhenglin Yang Xianjun Zhu Sichuan Provincial Key Laboratory for Human Disease Gene Study Department of Medical GeneticsSichuan Provincial People’s HospitalUniversity of Electronic Science and Technology of ChinaChengdu 610072China Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences(2019RU026) Sichuan Academy of Medical Sciences and Sichuan Provincial People’s HospitalChengdu 610072China Key Laboratory of Tibetan Medicine Research Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine ResearchNorthwest Institute of Plateau BiologyXining 810008China Department of Ophthalmology Shangqiu First People’s HospitalShangqiu 476000China Natural Products Research Center Institute of Chengdu BiologySichuan Translational Medicine HospitalChinese Academy of SciencesChengdu 610072China College of Life Sciences and Technology University of Electronic Science and Technology of ChinaChengdu 610072China

The endoplasmic reticulum(ER) membrane protein complex(emc) regulates the synthesis and quality control of membrane proteins with multiple transmembrane domains. One of the membrane spanning subunits, emc3, is a core member of the emc complex that provides essential hydrophilic vestibule for substrate insertion. Here, we show that the emc subunit emc3 plays critical roles in the retinal vascular angiogenesis by regulating Norrin/Wnt signaling. Postnatal endothelial cell(EC)-specific deletion of emc3 led to retarded retinal vascular development with a hyperpruned vascular network, the appearance of bluntended, aneurysm-like tip endothelial cells(ECs) with reduced numbers of filopodia and leakage of erythrocytes at the vascular front. Diminished tube formation and cell proliferation were also observed in emc3 depleted human retinal endothelial cells(HRECs). We then discovered a critical role for emc3 in expression of FZD4 receptor of β-catenin signaling using RNA sequencing, real-time quantitative PCR(RT-q PCR) and luciferase reporter assay. Moreover, augmentation of Wnt activity via lithium chloride(Li Cl) treatment remarkably enhanced β-catenin signaling and cell proliferation of HRECs. Additionally, Li Cl partially reversed the angiogenesis defects in emc3-c KO mice. Our data reveal that emc3 plays essential roles in angiogenesis through direct control of FZD4 expression and Norrin/β-catenin signaling.

关键词： ER membrane protein complex emc3 angiogenesis cell proliferation lithium chloride Wnt

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