DVL mutations identified from human neural tube defects and Dandy-Walker malformation obstruct the Wnt signaling pathway

被引:7
作者
Liu, Lingling [1 ,2 ]
Liu, Weiqi [1 ,2 ]
Shi, Yan [1 ]
Li, Ling [1 ]
Gao, Yunqian [1 ]
Lei, Yunping [3 ,4 ]
Finnell, Richard [1 ,3 ,4 ]
Zhang, Ting [5 ]
Zhang, Feng [1 ,2 ]
Jin, Li [1 ,2 ]
Li, Huili [8 ]
Tao, Wufan [1 ,9 ]
Wang, Hongyan [1 ,2 ,6 ,7 ]
机构
[1] Fudan Univ, Obstet & Gynecol Hosp, State Key Lab Genet Engn, Sch Life Sci, Shanghai 200011, Peoples R China
[2] Fudan Univ, Inst Reprod & Dev, NHC Key Lab Reprod, Shanghai Inst Planned Parenthood Res, Shanghai 200032, Peoples R China
[3] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[4] Baylor Coll Med, Dept Med, Houston, TX 77030 USA
[5] Capital Inst Pediat, Beijing 100020, Peoples R China
[6] Fudan Univ, Childrens Hosp, Shanghai 200032, Peoples R China
[7] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China
[8] Univ Colorado, Mol Cellular & Dev Biol, Boulder, CO 80309 USA
[9] Fudan Univ, Inst Dev Biol & Mol Med, Shanghai 200433, Peoples R China
基金
中国国家自然科学基金;
关键词
DVL genes; Mutation; NTD; Dandy-Walker malformation; Wnt pathway; CELL POLARITY GENE; CONVERGENT EXTENSION; RARE MUTATIONS; MICE; DEGRADATION; ANTAGONIST; VANGL2; CELSR1;
D O I
10.1016/j.jgg.2020.06.003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Wnt signaling pathways, including the canonical Wnt/beta-catenin pathway, planar cell polarity pathway, and Wnt/Ca2+ signaling pathway, play important roles in neural development during embryonic stages. The DVL genes encode the hub proteins for Wnt signaling pathways. The mutations in DVL2 and DVL3 were identified from patients with neural tube defects (NTDs), but their functions in the pathogenesis of human neural diseases remain elusive. Here, we sequenced the coding regions of three DVL genes in 176 stillborn or miscarried fetuses with NTDs or Dandy-Walker malformation (DWM) and 480 adult controls from a Han Chinese population. Four rare mutations were identified: DVL1 p.R558H, DVL1 p.R606C, DVL2 p.R633W, and DVL3 p.R222Q. To assess the effect of these mutations on NTDs and DWM, various functional analyses such as luciferase reporter assay, stress fiber formation, and in vivo teratogenic assay were performed. The results showed that the DVL2 p.R633W mutation destabilized DVL2 protein and upregulated activities for all three Wnt signalings (Wnt/beta-catenin signaling, Wnt/planar cell polarity signaling, and Wnt/Ca2+ signaling) in mammalian cells. In contrast, DVL1 mutants (DVL1 p.R558H and DVL1 p.R606C) decreased canonical Wnt/I3-catenin signaling but increased the activity of Wnt/Ca2+ signaling, and DVL3 p.R222Q only decreased the activity of Wnt/Ca2+ signaling. We also found that only the DVL2 p.R633W mutant displayed more severe teratogenicity in zebrafish embryos than wild-type DVL2. Our study demonstrates that these four rare DVL mutations, especially DVL2 p.R633W, may contribute to human neural diseases such as NTDs and DWM by obstructing Wnt signaling pathways. Copyright (C) 2020, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.
引用
收藏
页码:301 / 310
页数:10
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