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.