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Lrp6 介导的 Wnt/β-连环蛋白信号通路在小鼠脊髓神经管缺陷发生发展及干预中的作用。

The role of Lrp6-mediated Wnt/β-catenin signaling in the development and intervention of spinal neural tube defects in mice.

机构信息

Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children-Northern California, Department of Biochemistry and Molecular Medicine, University of California, Davis School of Medicine, Sacramento, CA 95817, USA.

出版信息

Dis Model Mech. 2022 Jun 1;15(6). doi: 10.1242/dmm.049517. Epub 2022 Jun 10.

DOI:10.1242/dmm.049517
PMID:35514236
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9194482/
Abstract

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.

摘要

神经管缺陷（NTDs）是常见且严重的出生缺陷之一，其病因尚未完全阐明。Wnt 共受体 LRP6 的突变与人类 NTDs 有关。Lrp6 的获得功能（GOF）或丧失功能（LOF）突变均可导致小鼠发生 NTDs。Lrp6-GOF 突变体中的 NTDs 可能归因于 β-连环蛋白非依赖性非经典 Wnt 信号的改变。然而，Lrp6-LOF 突变体中 NTDs 的机制以及 Lrp6 介导的经典 Wnt/β-连环蛋白信号在神经管闭合中的作用仍未解决。我们之前证明了β-连环蛋白信号对于后神经孔（PNP）闭合是必需的。在本研究中，条件性敲除背侧 PNP 中的 Lrp6 导致脊柱 NTDs，同时伴随着 Wnt/β-连环蛋白信号及其下游靶基因 Pax3 的活性降低，后者对于 PNP 闭合是必需的。β-连环蛋白 GOF 挽救了 Lrp6-LOF 突变体中的 NTDs。此外，通过恢复 Pax3 的表达，母体补充 Wnt/β-连环蛋白信号激动剂可减少 Lrp6-LOF 突变体中脊柱 NTDs 的频率和严重程度。综上所述，这些结果表明 Lrp6 介导的 Wnt/β-连环蛋白信号在 PNP 闭合中起着至关重要的作用，这也为通过操纵经典 Wnt/β-连环蛋白信号活性来干预 NTD 提供了一个治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f4/9194482/d50917df6bb3/dmm-15-049517-g8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f4/9194482/84aaa075cbed/dmm-15-049517-g1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f4/9194482/5ccccd61fb24/dmm-15-049517-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f4/9194482/8022612c3077/dmm-15-049517-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f4/9194482/d50917df6bb3/dmm-15-049517-g8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f4/9194482/84aaa075cbed/dmm-15-049517-g1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f4/9194482/afbb9acc3de4/dmm-15-049517-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f4/9194482/d5efd3a17eaf/dmm-15-049517-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f4/9194482/5ccccd61fb24/dmm-15-049517-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f4/9194482/8022612c3077/dmm-15-049517-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b6f4/9194482/d50917df6bb3/dmm-15-049517-g8.jpg

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