Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy.
Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy.
复制标题
DOI：
10.1016/j.gendis.2022.10.003
复制
发表时间：
2023-11
期刊：
影响因子：
6.8
通讯作者：
Zhu, Xianjun
中科院分区：
文献类型：
--
作者：
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
内质网(ER)膜蛋白复合体(EMC)是新合成的多跨膜蛋白共翻译插入所必需的。不同细胞类型的EMC功能受损与多种疾病有关。利用可诱导的遗传小鼠模型，我们发现了内皮细胞(EC)特异性缺失EMC最大亚基Emc1在视网膜血管形成中的缺陷。内皮细胞中Emc1的缺失导致血管进展和血管密度降低，尖端细胞发芽减少，血管渗漏。然后，我们对人视网膜微血管内皮细胞(HRECs)进行了无偏见的转录转录分析，揭示了EMc1在β-连环蛋白信号通路中的关键作用。进一步的体外和体内实验证明，缺失EMC1后，WnT受体FZD4的表达减少，从而导致β-连环蛋白信号转导活性降低，而该受体可被氯化锂处理后恢复。在这些发现的推动下，我们筛选了家族性渗出性玻璃体视网膜病变(FEVR)患者的基因组DNA样本，并在EMC1中发现了一个与FEVR表型共分离的杂合变异。体外表达实验表明，该变异等位基因不能促进FZD4在质膜上的表达，也不能激活β-连环蛋白信号通路，这可能是FEVR的一个主要原因。综上所述，我们的研究结果表明，EMC1基因的变异导致β-连环蛋白信号活性受损，这可能与FEVR的发病机制有关。
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.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
中国多中心新生儿眼部筛查项目早期发现眼部异常——一年结果
影响因子：
3.4
作者：
Fei P;Liu Z;He L;Li N;Xu L;Zhang M;Zhou Y;Li F;Wang H;Zhang Q;Huang Q;Li Y;Chen S;Guo W;Li Y;Liu Y;Lu J;Wang Y;Zhu X;Wang L;Wang Y;Xian J;Xu Y;Ji X;Liang T;Ren J;Zhang X;Li J;Zhao P
通讯作者：
Zhao P
卫星细胞中磷脂酰丝氨酸翻转酶β亚基Tmem30a的缺失导致骨骼肌再生延迟
影响因子：
4.9
作者：
Sun KX;Jiang XY;Li X;Su YJ;Wang JL;Zhang L;Yang YM;Zhu XJ
通讯作者：
Zhu XJ
影响因子：
64.5
作者：
Junge, Harald J.;Yang, Stacey;Ye, Weilan
通讯作者：
Ye, Weilan
影响因子：
9.8
作者：
Harel, Tamar;Yesil, Gozde;Lupski, James R.
通讯作者：
Lupski, James R.