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

Neural tube defects (NTDs) are a common and devastating birth defect. The current NTD rate in the U.S. reflects an approximately 30% decrease following folic acid (FA) supplementation in the 1990’s as a public health measure. Yet, questions remain including which gene mutations are sensitive to folic acid levels and how folic acid acts to alter NTD risk. We studied the relationship between FA dosage and NTD rates in NTD mouse models and propose that genes involved in cilia formation and function represent an FA sensitive ontology and a possible avenue for further reducing NTD rates. We demonstrate that in cilia mutant mice, a more moderate level of FA is beneficial in reducing NTD rates and promoting primary and motile cilia formation and function. 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.