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Nucleotide precursors prevent folic acid-resistant neural tube defects in the mouse

Leung, KY; De Castro, SC; Savery, D; Copp, AJ; Greene, ND; (2013) Nucleotide precursors prevent folic acid-resistant neural tube defects in the mouse. Brain: A Journal of Neurology , 136 (9) pp. 2836-2841. 10.1093/brain/awt209. Green open access


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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.

Type: Article
Title: Nucleotide precursors prevent folic acid-resistant neural tube defects in the mouse
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/brain/awt209
Publisher version: http://dx.doi.org/10.1093/brain/awt209
Language: English
Additional information: © The Author(s) 2013. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Curly tail, Embryo, Neural tube defects, Nucleotides, Spina bifida
URI: http://discovery.ucl.ac.uk/id/eprint/1395133
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