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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
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 def...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Chongqing Medical University
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10404869/ https://www.ncbi.nlm.nih.gov/pubmed/37554197 http://dx.doi.org/10.1016/j.gendis.2022.10.003 |
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author | Li, Shujin Yang, Mu Zhao, Rulian Peng, Li Liu, Wenjing Jiang, Xiaoyan He, Yunqi Dai, Erkuan Zhang, Lin Yang, Yeming Shi, Yi Zhao, Peiquan Yang, Zhenglin Zhu, Xianjun |
author_facet | Li, Shujin Yang, Mu Zhao, Rulian Peng, Li Liu, Wenjing Jiang, Xiaoyan He, Yunqi Dai, Erkuan Zhang, Lin Yang, Yeming Shi, Yi Zhao, Peiquan Yang, Zhenglin Zhu, Xianjun |
author_sort | Li, Shujin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10404869 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Chongqing Medical University |
record_format | MEDLINE/PubMed |
spelling | pubmed-104048692023-08-08 Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy Li, Shujin Yang, Mu Zhao, Rulian Peng, Li Liu, Wenjing Jiang, Xiaoyan He, Yunqi Dai, Erkuan Zhang, Lin Yang, Yeming Shi, Yi Zhao, Peiquan Yang, Zhenglin Zhu, Xianjun Genes Dis Full Length Article 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. Chongqing Medical University 2022-10-11 /pmc/articles/PMC10404869/ /pubmed/37554197 http://dx.doi.org/10.1016/j.gendis.2022.10.003 Text en © 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Full Length Article Li, Shujin Yang, Mu Zhao, Rulian Peng, Li Liu, Wenjing Jiang, Xiaoyan He, Yunqi Dai, Erkuan Zhang, Lin Yang, Yeming Shi, Yi Zhao, Peiquan Yang, Zhenglin Zhu, Xianjun Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy |
title | Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy |
title_full | Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy |
title_fullStr | Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy |
title_full_unstemmed | Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy |
title_short | Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy |
title_sort | defective emc1 drives abnormal retinal angiogenesis via wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy |
topic | Full Length Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10404869/ https://www.ncbi.nlm.nih.gov/pubmed/37554197 http://dx.doi.org/10.1016/j.gendis.2022.10.003 |
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