Neural Development Unit and Birth Defects Research Centre, Institute of Child Health, University College London, UK.
Brain. 2013 Sep;136(Pt 9):2836-41. doi: 10.1093/brain/awt209. Epub 2013 Aug 8.
Closure of the neural tube during embryogenesis is a crucial step in development of the central nervous system. Failure of this process results in neural tube defects, including spina bifida and anencephaly, which are among the most common birth defects worldwide. Maternal use of folic acid supplements reduces risk of neural tube defects but a proportion of cases are not preventable. Folic acid is thought to act through folate one-carbon metabolism, which transfers one-carbon units for methylation reactions and nucleotide biosynthesis. Hence suboptimal performance of the intervening reactions could limit the efficacy of folic acid. We hypothesized that direct supplementation with nucleotides, downstream of folate metabolism, has the potential to support neural tube closure. Therefore, in a mouse model that exhibits folic acid-resistant neural tube defects, we tested the effect of specific combinations of pyrimidine and purine nucleotide precursors and observed a significant protective effect. Labelling in whole embryo culture showed that nucleotides are taken up by the neurulating embryo and incorporated into genomic DNA. Furthermore, the mitotic index was elevated in neural folds and hindgut of treated embryos, consistent with a proposed mechanism of neural tube defect prevention through stimulation of cellular proliferation. These findings may provide an impetus for future investigations of supplemental nucleotides as a means to prevent a greater proportion of human neural tube defects than can be achieved by folic acid alone.
胚胎发生过程中神经管的闭合是中枢神经系统发育的关键步骤。这一过程的失败会导致神经管缺陷，包括脊柱裂和无脑畸形，这些缺陷是全球最常见的出生缺陷之一。母体使用叶酸补充剂可以降低神经管缺陷的风险，但仍有一部分病例无法预防。叶酸被认为通过叶酸一碳代谢发挥作用，该代谢将一碳单位转移用于甲基化反应和核苷酸生物合成。因此，中间反应的表现不佳可能会限制叶酸的功效。我们假设，直接补充叶酸代谢下游的核苷酸有可能支持神经管闭合。因此，在一种表现出叶酸抗性神经管缺陷的小鼠模型中，我们测试了嘧啶和嘌呤核苷酸前体的特定组合的效果，观察到了显著的保护作用。在整个胚胎培养中的标记显示，核苷酸被正在神经化的胚胎吸收，并整合到基因组 DNA 中。此外，处理胚胎的神经褶和后肠中的有丝分裂指数升高，这与通过刺激细胞增殖来预防神经管缺陷的提议机制一致。这些发现可能为未来研究补充核苷酸作为一种手段来预防比叶酸单独使用更多的人类神经管缺陷提供动力。
