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 implicat...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 theβ-catenin signaling pathway.Further in-vitro and in-vivo experiments proved that loss of EMC1 led to compromisedβ-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 theβ-catenin signaling pathway,which might be a main cause of FEVR.In conclusion,our findings reveal that variants in EMC1 gene cause compromisedβ-catenin signaling activity,which may be associated with the pathogenesis of FEVR.展开更多
基金supported by the National Natural Science Foundation of China(No.82101153,82000913,81970841,82121003,and 82071009)the Sichuan Science and Technology Program,China(No.2022YFS0598,2021YFS0386,2021YFS0369,and 2021JDGD0036)+4 种基金the CAMS Innovation Fund for Medical Sciences,China(No.2019-12M-5-032)the Department of Science and Technology of Qinghai Province,China(No.2022-HZ-814)the fund for Sichuan Provincial People's Hospital,China(No.2021QN01)the Department of Chengdu Science and Technology,China(No.2021-YF05-01316-SN)the Huanhua Outstanding Scholar Program for Sichuan Provincial People's Hospital(China)to Xianjun Zhu.The funders had no role in the study design,data collection,analysis,or preparation of the manuscript.
文摘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 theβ-catenin signaling pathway.Further in-vitro and in-vivo experiments proved that loss of EMC1 led to compromisedβ-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 theβ-catenin signaling pathway,which might be a main cause of FEVR.In conclusion,our findings reveal that variants in EMC1 gene cause compromisedβ-catenin signaling activity,which may be associated with the pathogenesis of FEVR.
