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

	Defective EMC1 drives abnormal retinal angiogenesis via Wnt/b-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
刊名	GENES & DISEASES
	2023
卷号	10 期号:6 页码:2572
英文摘要	Endoplasmic reticulum (ER) membrane protein complex (EMC) is required for the cotranslational 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 13-catenin signaling pathway. Further in-vitro and in-vivo experiments proved that loss of EMC1 led to compromised 13-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 13-catenin signaling pathway, which might be a main cause of FEVR. In conclusion, our findings reveal that variants in EMC1 gene cause compromised 13-catenin signaling activity, which may be associated with the pathogenesis of FEVR. 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
内容类型	期刊论文
源URL	[http://210.75.249.4/handle/363003/61552]
专题	西北高原生物研究所_中国科学院西北高原生物研究所
推荐引用方式 GB/T 7714	Li, Shujin,Yang, Mu,Zhao, Rulian,et al. Defective EMC1 drives abnormal retinal angiogenesis via Wnt/b-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy[J]. GENES & DISEASES,2023,10(6):2572.
APA	Li, Shujin.,Yang, Mu.,Zhao, Rulian.,Peng, Li.,Liu, Wenjing.,...&Zhu, Xianjun.(2023).Defective EMC1 drives abnormal retinal angiogenesis via Wnt/b-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy.GENES & DISEASES,10(6),2572.
MLA	Li, Shujin,et al."Defective EMC1 drives abnormal retinal angiogenesis via Wnt/b-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy".GENES & DISEASES 10.6(2023):2572.