The role of Lrp6-mediated Wnt/β-catenin signaling in the development and intervention of spinal neural tube defects in mice.
The role of Lrp6-mediated Wnt/β-catenin signaling in the development and intervention of spinal neural tube defects in mice.
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DOI：
10.1242/dmm.049517
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发表时间：
2022-06-01
影响因子：
4.3
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中科院分区：
文献类型：
--
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神经管缺陷（NTDs）是常见的和严重的出生缺陷，病因知之甚少。Wnt共受体LRP 6的突变与人类NTD相关。Lrp 6的功能获得性（GOF）或功能丧失性（LOF）突变均可导致小鼠NTD。Lrp 6-GOF突变体中的NTD可能归因于改变的β-连环蛋白非依赖性非经典Wnt信号传导。然而，Lrp 6-LOF突变体中NTD的潜在机制以及Lrp 6介导的经典Wnt/β-catenin信号传导在神经管闭合中的作用仍然没有得到解决。我们以前证明，β-连环蛋白信号是必需的后神经孔（PNP）关闭。在目前的研究中，在背侧PNP中条件性消融Lrp 6导致脊髓NTD，Wnt/β-catenin信号传导及其下游靶基因Pax 3的活性降低，这是PNP闭合所需的。β-连环蛋白-GOF拯救Lrp 6-LOF突变体中的NTD。此外，母体补充Wnt/β-连环蛋白信号激动剂通过恢复Pax 3表达降低了Lrp 6-LOF突变体中脊髓NTD的频率和严重程度。总之，这些结果证明了Lrp 6介导的Wnt/β-连环蛋白信号传导在PNP闭合中的重要作用，这也可以通过操纵经典Wnt/β-连环蛋白信号传导活性为NTD干预提供治疗靶标。总结：背神经褶皱中Lrp 6的条件性消融导致脊髓神经管缺陷，这可以通过β-连环蛋白的遗传激活或母体补充Wnt信号传导激动剂来挽救。
Neural tube defects (NTDs) are among the common and severe birth defects with poorly understood etiology. Mutations in the Wnt co-receptor LRP6 are associated with NTDs in humans. Either gain-of-function (GOF) or loss-of-function (LOF) mutations of Lrp6 can cause NTDs in mice. NTDs in Lrp6-GOF mutants may be attributed to altered β-catenin-independent noncanonical Wnt signaling. However, the mechanisms underlying NTDs in Lrp6-LOF mutants and the role of Lrp6-mediated canonical Wnt/β-catenin signaling in neural tube closure remain unresolved. We previously demonstrated that β-catenin signaling is required for posterior neuropore (PNP) closure. In the current study, conditional ablation of Lrp6 in dorsal PNP caused spinal NTDs with diminished activities of Wnt/β-catenin signaling and its downstream target gene Pax3, which is required for PNP closure. β-catenin-GOF rescued NTDs in Lrp6-LOF mutants. Moreover, maternal supplementation of a Wnt/β-catenin signaling agonist reduced the frequency and severity of spinal NTDs in Lrp6-LOF mutants by restoring Pax3 expression. Together, these results demonstrate the essential role of Lrp6-mediated Wnt/β-catenin signaling in PNP closure, which could also provide a therapeutic target for NTD intervention through manipulation of canonical Wnt/β-catenin signaling activities. Summary: Conditional ablation of Lrp6 in dorsal neural folds causes spinal neural tube defects that can be rescued by genetic activation of β-catenin or maternal supplementation of Wnt signaling agonists.
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