Mouse models provide opportunities to investigate genetic interactions that cause or modify the frequency of neural tube defects (NTDs). Mutation of the PAX3 transcription factor prevents neural tube closure, leading to cranial and spinal NTDs whose frequency is responsive to folate status. Canonical Wnt signalling is implicated both in regulation of Pax3 expression and as a target of PAX3. This study investigated potential interactions of Pax3 mutation and canonical Wnt signalling using conditional gain- and loss-of-function models of β-catenin. We found an additive effect of β-catenin gain of function and Pax3 loss of function on NTDs and neural crest defects. β-catenin gain of function in the Pax3 expression domain led to significantly increased frequency of cranial but not spinal NTDs in embryos that are heterozygous for Pax3 mutation, while both cranial and spinal neural tube closure were exacerbated in Pax3 homozygotes. Similarly, deficits of migrating neural crest cells were exacerbated by β-catenin gain of function, with almost complete ablation of spinal neural crest cells and derivatives in Pax3 homozygous mutants. Pax3 expression was not affected by β-catenin gain of function, while we confirmed that loss of function led to reduced Pax3 transcription. In contrast to gain of function, β-catenin knockout in the Pax3 expression domain lowered the frequency of cranial NTDs in Pax3 null embryos. However, loss of function of β-catenin and Pax3 resulted in spinal NTDs, suggesting differential regulation of cranial and spinal neural tube closure. In summary, β-catenin function modulates the frequency of PAX3-related NTDs in the mouse.

中文翻译：

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Pax3突变和经典Wnt信号的遗传相互作用调节神经管缺陷和神经嵴异常

小鼠模型提供了研究导致或改变神经管缺陷 (NTD) 频率的遗传相互作用的机会。PAX3 转录因子的突变可防止神经管闭合，导致颅和脊髓 NTD，其频率对叶酸状态有反应。规范 Wnt 信号传导涉及Pax3表达的调节和作为 PAX3 的目标。本研究使用 β-连环蛋白的条件增益和功能丧失模型研究了Pax3突变和经典 Wnt 信号传导的潜在相互作用。我们发现了 β-catenin 功能增益和Pax3功能丧失对 NTD 和神经嵴缺陷的累加效应。β-连环蛋白在Pax3中的功能增益表达结构域导致Pax3突变杂合子胚胎中颅脑 NTDs 的频率显着增加，而脊髓 NTDs 的频率显着增加，而在Pax3纯合子中颅神经管和脊髓神经管闭合都加剧了。同样，迁移神经嵴细胞的缺陷因 β-连环蛋白功能获得而加剧，在Pax3纯合突变体中几乎完全消融脊髓神经嵴细胞和衍生物。Pax3表达不受 β-catenin 功能获得的影响，而我们证实功能丧失导致Pax3转录减少。与功能获得相比， Pax3中的 β-连环蛋白敲除表达域降低了Pax3空胚胎中颅 NTD 的频率。然而，β-连环蛋白和Pax3的功能丧失导致脊髓 NTD，表明颅神经管和脊髓神经管闭合的差异调节。总之，β-连环蛋白功能调节小鼠 PAX3 相关 NTD 的频率。