Weiqi Liu
Yan Shi
Ling Li
Yunqian Gao
Yunping Lei
Richard Finnell
Ting Zhang
Feng Zhang
Li Jin
Huili Li
Wufan Tao
Hongyan Wang
aObstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, 200011, China
bNHC Key Lab of Reproduction (Shanghai Institute of Planned Parenthood Research), Institute of Reproduction and Development, Fudan University, Shanghai, 200032, China
cDepartments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
dCapital Institute of Pediatrics, Beijing, 100020, China
eChildren's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
fMolecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA
gInsititute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai, 200433, China
More InformationCorresponding author: E-mail address: lihuili2011@gmail.com (Huili Li);E-mail address: wufan_tao@fudan.edu.cn (Wufan Tao);E-mail address: wanghy@fudan.edu.cn (Hongyan Wang)
Publish Date:2020-06-25
Abstract
Abstract
Wnt signaling pathways, including the canonical Wnt/β-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/β-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/β-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.Keywords: Mutation,
NTD,
Dandy-Walker malformation,
Wnt pathway
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http://www.jgenetgenomics.org/article/exportPdf?id=b522908d-983e-42c2-a4f6-0847475f84fa&language=en
