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

Wnt信号通路 衣冠不整 神经管 干瘪的 生物 LRP6型 斑马鱼 连环蛋白 信号转导 收敛扩展 LRP5 细胞生物学 连环素 WNT3A型 遗传学 癌症研究 胚胎干细胞 基因 胚胎 原肠化
作者
Lingling Liu,Weiqi Liu,Shi Yan,Ling Li,Yun‐Qian Gao,Yunping Lei,Richard H. Finnell,Ting Zhang,Feng Zhang,Jin Li,Huili Li,Wufan Tao,Hongyan Wang
出处
期刊:Journal of Genetics and Genomics [Elsevier]
卷期号:47 (6): 301-310 被引量:9
标识
DOI:10.1016/j.jgg.2020.06.003
摘要

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.
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