UC San Diego

Neural tube defects (NTDs) are developmental malformations caused by incomplete closure of the neural tube (NT), a precursor of brain and spinal cord during development. Sufficient periconceptional levels of folic acid (FA) through supplementation in humans significantly reduces the risk of NTDs. Nevertheless, the underlying mechanism by which FA alleviates the risk of NTDs still remains unknown. Multiple genes have been implicated in NTDs making it difficult to outline a specific mechanism that may cause NTD. FA plays critical roles in single carbon metabolism, required for production of nucleotides and methylation through the intermediary S-adenosyl methionine. We found that murine dams treated with low periconceptional FA had embryos with fewer somites than normal FA condition. Therefore, we investigated how FA affects the rate of somite formation and how this in turn may affect NT closure. We differentiated mouse epiblast stem cells (mEPiSCs) to presomitic mesodermal (PSM) tissue that is known to segment and produce somites and monitored the expression pattern of segmentation clock marker gene HES7. Inhibiting FA pathway with methotrexate during the PSM induction decreased the amplitude of HES7 cycling. We found that treating these PSM cells with methionine increases the HES7 cycling amplitude. Thus, FA may exert its effect on NTD risk through regulation of key metabolites including methionine that could impact somitogenesis.