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

Shujin Li; Mu Yang; Rulian Zhao; Li Peng; Wenjing Liu; Xiaoyan Jiang; Yunqi He; Erkuan Dai; Lin Zhang; Yeming Yang; Yi Shi; Peiquan Zhao; Zhenglin Yang; Xianjun Zhu

doi:10.1016/j.gendis.2022.10.003

您当前的位置：

首页 >

文章列表页 >

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

Full Length Articles | 更新时间：2024-02-04

- 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
- Genes & Diseases 2023年1卷第6期页码：2572-2585
- 作者机构：
  
  1. The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China,Sichuan,Chengdu,China,610072
  2. Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital,Sichuan,Chengdu,China,610072
  3. Department of Ophthalmology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,China,200092
  4. Key Laboratory of Tibetan Medicine Research, Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology,Qinghai,Xining,China,810008
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2022.10.003
  中图分类号：
- 纸质出版日期：2023，
  
  网络出版日期：2023-11-1，
扫描看全文
Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy[J]. Genes & Diseases, 2023,1(6):2572-2585.

Shujin Li, Mu Yang, Rulian Zhao, et al. Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy[J]. Genes & Diseases, 2023,1(6):2572-2585.
Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy[J]. Genes & Diseases, 2023,1(6):2572-2585. DOI： 10.1016/j.gendis.2022.10.003.

Shujin Li, Mu Yang, Rulian Zhao, et al. Defective EMC1 drives abnormal retinal angiogenesis via Wnt/β-catenin signaling and may be associated with the pathogenesis of familial exudative vitreoretinopathy[J]. Genes & Diseases, 2023,1(6):2572-2585. DOI： 10.1016/j.gendis.2022.10.003.

摘要

Abstract

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.

关键词

Keywords

Angiogenesisβ-catenin signalingEMC1Familial exudative vitreoretinopathyLiCl

references

1 P. CarmelietAngiogenesis in health and disease Nat Med, 9 (6) (2003), pp. 653-660

2 B. Xue, P. Wang, W. Yu, et al.CD146 as a promising therapeutic target for retinal and choroidal neovascularization diseases Sci China Life Sci, 65 (6) (2022), pp. 1157-1170

3 W. Liu, X. Jiang, X. Li, et al.LMBR1L regulates the proliferation and migration of endothelial cells through Norrin/β-catenin signaling J Cell Sci, 135 (6) (2022), p. jcs259468

4 Y. Qian, Z. Wang, H. Lin, et al.TRIM47 is a novel endothelial activation factor that aggravates lipopolysaccharide-induced acute lung injury in mice via K63-linked ubiquitination of TRAF2 Signal Transduct Targeted Ther, 7 (1) (2022), p. 148

5 A.M. Simon, A.R. McWhorterVascular abnormalities in mice lacking the endothelial gap junction proteins connexin37 and connexin40 Dev Biol, 251 (2) (2002), pp. 206-220

6 H.J. Junge, S. Yang, J.B. Burton, et al.TSPAN12 regulates retinal vascular development by promoting norrin- but not wnt-induced FZD4/β-catenin signaling Cell, 139 (2) (2009), pp. 299-311

7 M.E. Yeager, G.R. Halley, H.A. Golpon, et al.Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension Circ Res, 88 (1) (2001), pp. E2-E11

8 V.G. Criswick, C.L. SchepensFamilial exudative vitreoretinopathy Am J Ophthalmol, 68 (4) (1969), pp. 578-594

9 P. Fei, Z. Liu, L. He, et al.Early detection of ocular abnormalities in a Chinese multicentre neonatal eye screening programme-1-year result Acta Ophthalmol, 99 (3) (2021), pp. e415-e422

10 M. Yang, S. Li, L. Huang, et al.CTNND1 variants cause familial exudative vitreoretinopathy through the Wnt/cadherin axis JCI Insight, 7 (14) (2022), Article e158428

11 C.A. Franco, S. Liebner, H. GerhardtVascular morphogenesis: a Wnt for every vessel? Curr Opin Genet Dev, 19 (5) (2009), pp. 476-483

12 V.A.M. van de Schans, J.F. Smits, W.M. BlankesteijnThe Wnt/frizzled pathway in cardiovascular development and disease: friend or foe? Eur J Pharmacol, 585 (2–3) (2008), pp. 338-345

13 M. Zerlin, M.A. Julius, J. KitajewskiWnt/frizzled signaling in angiogenesis Angiogenesis, 11 (1) (2008), pp. 63-69

14 X. Yan, Z. Yang, Y. Chen, et al.Endothelial cells-targeted soluble human Delta-like 4 suppresses both physiological and pathological ocular angiogenesis Sci China Life Sci, 58 (5) (2015), pp. 425-431

15 B.T. MacDonald, K. Tamai, X. HeWnt/β-catenin signaling: components, mechanisms, and diseases Dev Cell, 17 (1) (2009), pp. 9-26

16 M. Yang, S. Li, W. Liu, et al.The ER membrane protein complex subunit Emc3 controls angiogenesis via the FZD4/WNT signaling axis Sci China Life Sci, 64 (11) (2021), pp. 1868-1883

17 Y. He, M. Yang, R. Zhao, et al.Novel truncating variants in CTNNB1 cause familial exudative vitreoretinopathy J Med Genet, 60 (2) (2023), pp. 174-182

18 Q. Xu, Y. Wang, A. Dabdoub, et al.Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair Cell, 116 (6) (2004), pp. 883-895

19 S. Li, M. Yang, Y. He, et al.Variants in the Wnt co-receptor LRP6 are associated with familial exudative vitreoretinopathy J Genet Genomics, 49 (6) (2022), pp. 590-594

20 R. Zhao, S. Wang, P. Zhao, et al.Heterozygote loss-of-function variants in the LRP5 gene cause familial exudative vitreoretinopathy Clin Exp Ophthalmol, 50 (4) (2022), pp. 441-448

21 M.C. Jonikas, S.R. Collins, V. Denic, et al.Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum Science, 323 (5922) (2009), pp. 1693-1697

22 N. Volkmar, M.L. Thezenas, S.M. Louie, et al.The ER membrane protein complex promotes biogenesis of sterol-related enzymes maintaining cholesterol homeostasis J Cell Sci, 132 (2) (2019), p. jcs223453

23 P.J. Chitwood, R.S. HegdeThe role of EMC during membrane protein biogenesis Trends Cell Biol, 29 (5) (2019), pp. 371-384

24 A. Guna, N. Volkmar, J.C. Christianson, et al.The ER membrane protein complex is a transmembrane domain insertase Science, 359 (6374) (2018), pp. 470-473

25 M.J. Shurtleff, D.N. Itzhak, J.A. Hussmann, et al.The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins Elife, 7 (2018), Article e37018

26 P.J. Chitwood, S. Juszkiewicz, A. Guna, et al.EMC is required to initiate accurate membrane protein topogenesis Cell, 175 (6) (2018), pp. 1507-1519 e16

27 G. Kauffenstein, I. Laher, K. Matrougui, et al.Emerging role of G protein-coupled receptors in microvascular myogenic tone Cardiovasc Res, 95 (2) (2012), pp. 223-232

28 D. Mehta, A.B. MalikSignaling mechanisms regulating endothelial permeability Physiol Rev, 86 (1) (2006), pp. 279-367

29 L. Abu-Safieh, M. Alrashed, S. Anazi, et al.Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes Genome Res, 23 (2) (2013), pp. 236-247

30 T. Harel, G. Yesil, Y. Bayram, et al.Monoallelic and biallelic variants in EMC1 identified in individuals with global developmental delay, hypotonia, scoliosis, and cerebellar atrophy Am J Hum Genet, 98 (3) (2016), pp. 562-570

31 T.S. Geetha, L. Lingappa, A.R. Jain, et al.A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy Mol Genet Genomic Med, 6 (2) (2018), pp. 282-287

32 S. Cabet, G. Lesca, A. Labalme, et al.Novel truncating and missense variants extending the spectrum of EMC1-related phenotypes, causing autism spectrum disorder, severe global development delay and visual impairment Eur J Med Genet, 63 (6) (2020), Article 103897

33 J. Marquez, J. Criscione, R.M. Charney, et al.Disrupted ER membrane protein complex-mediated topogenesis drives congenital neural crest defects J Clin Invest, 130 (2) (2020), pp. 813-826

34 A. Fraccaroli, B. Pitter, A.A. Taha, et al.Endothelial alpha-parvin controls integrity of developing vasculature and is required for maintenance of cell-cell junctions Circ Res, 117 (1) (2015), pp. 29-40

35 L. Zhang, S.S. Zhang, K.F. Wang, et al.Overexpression of Twist1 in vascular endothelial cells promotes pathological retinal angiogenesis in mice Zool Res, 43 (1) (2022), pp. 64-74

36 K.X. Sun, X.Y. Jiang, X. Li, et al.Deletion of phosphatidylserine flippase β-subunit Tmem30a in satellite cells leads to delayed skeletal muscle regeneration Zool Res, 42 (5) (2021), pp. 650-659

37 O. Contreras-López, T.C. Moyano, D.C. Soto, et al.Step-by-step construction of gene Co-expression networks from high-throughput Arabidopsis RNA sequencing data Methods Mol Biol, 1761 (2018), pp. 275-301

38 F. García-Alcalde, K. Okonechnikov, J. Carbonell, et al.Qualimap: evaluating next-generation sequencing alignment data Bioinformatics, 28 (20) (2012), pp. 2678-2679

39 S. Anders, P.T. Pyl, W. HuberHTSeq—a Python framework to work with high-throughput sequencing data Bioinformatics, 31 (2) (2014), pp. 166-169

40 M.D. Robinson, D.J. McCarthy, G.K. SmythedgeR: a Bioconductor package for differential expression analysis of digital gene expression data Bioinformatics, 26 (1) (2009), pp. 139-140

41 D.J. McCarthy, Y. Chen, G.K. SmythDifferential expression analysis of multifactor RNA-Seq experiments with respect to biological variation Nucleic Acids Res, 40 (10) (2012), pp. 4288-4297

42 H. Mi, A. Muruganujan, D. Ebert, et al.PANTHER version 14:more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools Nucleic Acids Res, 47 (D1) (2018), pp. D419-D426

43 H. Li, R. DurbinFast and accurate short read alignment with Burrows-Wheeler transform Bioinformatics, 25 (14) (2009), pp. 1754-1760

44 S. Selvam, T. Kumar, M. FruttigerRetinal vasculature development in health and disease Prog Retin Eye Res, 63 (2018), pp. 1-19

45 X. Ye, Y. Wang, H. Cahill, et al.Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization Cell, 139 (2) (2009), pp. 285-298

46 X. Zhu, M. Yang, P. Zhao, et al.Catenin α 1 mutations cause familial exudative vitreoretinopathy by overactivating Norrin/β-catenin signaling J Clin Invest, 131 (6) (2021), Article e139869

47 H. Park, H. Yamamoto, L. Mohn, et al.Integrin-linked kinase controls retinal angiogenesis and is linked to Wnt signaling and exudative vitreoretinopathy Nat Commun, 10 (1) (2019), p. 5243

48 Y. Wang, P.M. Smallwood, J. Williams, et al.A mouse model for kinesin family member 11 (Kif11)-associated familial exudative vitreoretinopathy Hum Mol Genet, 29 (7) (2020), pp. 1121-1131

49 T. Golan, A. Yaniv, A. Bafico, et al.The human Frizzled 6 (HFz6) acts as a negative regulator of the canonical Wnt. beta-catenin signaling cascade J Biol Chem, 279 (15) (2004), pp. 14879-14888

50 R. Nusse, H. CleversWnt/β-catenin signaling, disease, and emerging therapeutic modalities Cell, 169 (6) (2017), pp. 985-999

51 S.H. Seo, Y.S. Yu, S.W. Park, et al.Molecular characterization of FZD4, LRP5, and TSPAN12 in familial exudative vitreoretinopathy Invest Ophthalmol Vis Sci, 56 (9) (2015), pp. 5143-5151

52 C. Chen, Z. Wang, L. Sun, et al.Next-generation sequencing in the familial exudative vitreoretinopathy-associated rhegmatogenous retinal detachment Invest Ophthalmol Vis Sci, 60 (7) (2019), pp. 2659-2666

53 T. Tian, C. Chen, X. Zhang, et al.Clinical and genetic features of familial exudative vitreoretinopathy with only-unilateral abnormalities in a Chinese cohort JAMA Ophthalmol, 137 (9) (2019), pp. 1054-1058

查看原文

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

The journey towards physiology and pathology: Tracing the path of neuregulin 4

HIF-1α signaling: Essential roles in tumorigenesis and implications in targeted therapies

Mechanistic insight into lysyl oxidase in vascular remodeling and angiogenesis

LncRNA H19 mediates BMP9-induced angiogenesis in mesenchymal stem cells by promoting the p53-Notch1 angiogenic signaling axis

JAG1 enhances angiogenesis in triple-negative breast cancer through promoting the secretion of exosomal lncRNA MALAT1