Moderate levels of folic acid benefit outcomes for cilia based neural tube defects

Folic acid (FA) supplementation is a potent tool to reduce devastating birth defects known as neural tube defects (NTDs). Though effective, questions remain how FA achieves its protective effect and which gene mutations are sensitive to folic acid levels. We explore the relationship between FA dosage and NTD rates using NTD mouse models. We demonstrate that NTD rates in mouse models harboring mutations in cilia genes depend on FA dosage. Cilia mutant mouse models demonstrate reductions in NTD rates when exposed to moderate levels of FA that are not observed at higher fortified levels of FA. This trend continues with a moderate level of FA being beneficial for primary and motile cilia formation. We present a mechanism through which fortified FA levels reduce basal levels of reactive oxygen species (ROS) which in turn reduces ROS-sensitive GTPase activity required for ciliogenesis. Our data indicates that genes involved in cilia formation and function represent a FA sensitive category of mutations and a possible avenue for further reducing NTD and ciliopathy incidences.