摘要
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.
基金
This work was supported by the National Natural Science Foundation of China(81970841,81770950,81790643,82000913,and 82071009)
the Department of Science and Technology of Sichuan Province(2020JDZH0027 and 2020ZYD037)
the CAMS Innovation Fund for Medical Sciences(2019-12M-5-032)
the fund for Sichuan Provincial People’s Hospital(2021QN01)
the Chengdu Science and Technology Bureau(2019-YF05-00572-SN).
