β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation
β-catenin regulates Pax3 and Cdx2 for caudal neural tube closure and elongation
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DOI：
10.1242/dev.101550
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发表时间：
2014-01-01
期刊：
影响因子：
4.6
通讯作者：
Zhou, Chengji J.
中科院分区：
文献类型：
--
作者：
Zhao, Tianyu;Gan, Qini;Zhou, Chengji J.
非经典Wnt/平面细胞极性（PCP）信号在驱动神经管闭合和体轴伸长的会聚延伸中起主要作用。PCP信号基因突变导致严重的神经管缺陷（NTD）。然而，经典Wnt/β-连环蛋白信号传导在神经管闭合和NTDs中的作用仍然知之甚少。这项研究表明，在小鼠胚胎的背神经褶皱中的β-连环蛋白的条件性基因靶向抑制在背后神经孔（PNP）的含同源框基因Pax 3和Cdx 2的表达，随后减少在尾芽的Wnt/β-连环蛋白信号传导靶基因T、Tbx 6和Fgf 8的表达，导致脊柱裂开放，尾轴弯曲和尾截短。我们证明Pax 3和Cdx 2是Wnt/β-catenin信号转导的新下游靶点。Pax 3 cDNA的转基因激活可以挽救β-连环蛋白突变体中的闭合缺陷，表明Pax 3是PNP闭合过程中β-连环蛋白信号传导的关键下游效应子。Cdx 2是已知的是至关重要的后轴伸长和神经管关闭。我们发现Cdx 2的表达也被抑制在背PNPs的Pax 3无效的胚胎。然而，异位激活的Pax 3在β-连环蛋白突变体不能恢复Cdx 2 mRNA在背侧PNP，这表明β-连环蛋白和Pax 3的存在下，区域Cdx 2的表达是必需的。因此，β-连环蛋白信号传导是尾神经管闭合和伸长所必需的，通过PNP中关键靶基因的转录调节起作用。
Non-canonical Wnt/planar cell polarity (PCP) signaling plays a primary role in the convergent extension that drives neural tube closure and body axis elongation. PCP signaling gene mutations cause severe neural tube defects (NTDs). However, the role of canonical Wnt/beta-catenin signaling in neural tube closure and NTDs remains poorly understood. This study shows that conditional gene targeting of beta-catenin in the dorsal neural folds of mouse embryos represses the expression of the homeobox-containing genes Pax3 and Cdx2 at the dorsal posterior neuropore (PNP), and subsequently diminishes the expression of the Wnt/beta-catenin signaling target genes T, Tbx6 and Fgf8 at the tail bud, leading to spina bifida aperta, caudal axis bending and tail truncation. We demonstrate that Pax3 and Cdx2 are novel downstream targets of Wnt/beta-catenin signaling. Transgenic activation of Pax3 cDNA can rescue the closure defect in the beta-catenin mutants, suggesting that Pax3 is a key downstream effector of beta-catenin signaling in the PNP closure process. Cdx2 is known to be crucial in posterior axis elongation and in neural tube closure. We found that Cdx2 expression is also repressed in the dorsal PNPs of Pax3-null embryos. However, the ectopically activated Pax3 in the beta-catenin mutants cannot restore Cdx2 mRNA in the dorsal PNP, suggesting that the presence of both beta-catenin and Pax3 is required for regional Cdx2 expression. Thus, beta-catenin signaling is required for caudal neural tube closure and elongation, acting through the transcriptional regulation of key target genes in the PNP.