Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway
Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway
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DOI：
10.1093/hmg/ddt558
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发表时间：
2014-04-01
影响因子：
3.5
通讯作者：
Kibar, Zoha
中科院分区：
文献类型：
--
作者：
Allache, Redouane;Lachance, Stephanie;Kibar, Zoha
Wnt信号被分为典型的Wnt/ β -连环蛋白依赖通路和非典型的平面细胞极性（PCP）通路。这两种途径的失调分别主要与癌症或神经管缺陷（NTDs）有关。这两种途径似乎相互拮抗，最近的研究表明，一些分子开关可以激活一种途径，同时抑制另一种途径，从而部分介导这种拮抗作用。脂蛋白受体相关蛋白Lrp6对Wnt/ β -连环蛋白通路的激活至关重要，但其在Wnt/PCP信号传导中的功能仍不清楚。在这项研究中，我们研究了Lrp6作为一种新的ENU小鼠Lrp6突变体（Skax26(m1Jus)）和人类NTDs中Wnt通路之间的分子开关的作用。我们证明，Skax26（m1Jus）是Lrp6的一个高态等位基因，其Wnt规范性增加，pcp诱导的JNK活性降低。我们还发现Lrp6（Skax26-Jus）与PCP突变体（Vangl2(Lp)）遗传相互作用，其中双杂合子显示耳蜗毛细胞极性缺陷和NTDs频率增加。重要的是，我们的研究还证明了LRP6中罕见和新型错义突变的关联，LRP6是PCP途径与人类NTDs的抑制剂而不是激活剂。我们发现，NTDs中的三个LRP6突变导致Wnt典型活性降低，PCP信号传导增强。我们的数据证实了Lrp6在神经发育过程中对PCP信号传导的抑制作用，并表明在这一过程中，两个Wnt通路之间的严格调控和高度剂量敏感的拮抗作用的重要性。
Wnt signaling has been classified as canonical Wnt/beta-catenin-dependent or non-canonical planar cell polarity (PCP) pathway. Misregulation of either pathway is linked mainly to cancer or neural tube defects (NTDs), respectively. Both pathways seem to antagonize each other, and recent studies have implicated a number of molecular switches that activate one pathway while simultaneously inhibiting the other thereby partially mediating this antagonism. The lipoprotein receptor-related protein Lrp6 is crucial for the activation of the Wnt/beta-catenin pathway, but its function in Wnt/PCP signaling remains largely unknown. In this study, we investigate the role of Lrp6 as a molecular switch between both Wnt pathways in a novel ENU mouse mutant of Lrp6 (Skax26(m1Jus)) and in human NTDs. We demonstrate that Skax26(m1Jus) represents a hypermorphic allele of Lrp6 with increased Wnt canonical and abolished PCP-induced JNK activities. We also show that Lrp6(Skax26-Jus) genetically interacts with a PCP mutant (Vangl2(Lp)) where double heterozygotes showed an increased frequency of NTDs and defects in cochlear hair cells' polarity. Importantly, our study also demonstrates the association of rare and novel missense mutations in LRP6 that is an inhibitor rather than an activator of the PCP pathway with human NTDs. We show that three LRP6 mutations in NTDs led to a reduced Wnt canonical activity and enhanced PCP signaling. Our data confirm an inhibitory role of Lrp6 in PCP signaling in neurulation and indicate the importance of a tightly regulated and highly dosage-sensitive antagonism between both Wnt pathways in this process.