Folic acid prevention of neural tube defects requires retinoic acid produced by ALDH1L1

Folic acid (FA) supplementation during pregnancy is the commonly accepted treatment to prevent neurodevelopmental defects. The mechanism by which FA prevents neural tube defects (NTDs) remains unclear. FA also prevents other developmental malformations, including the alcohol-induced malformations in Fetal Alcohol Syndrome models. We show that FA acts through a metabolic link to retinoic acid (RA) signaling. Using a pax3-knockdown Xenopus model of FA-rescueable NTDs, we show that RA or its precursors equally rescue these defects. Similarly, FA rescues alcohol-induced NTDs in a model previously shown to be rescued by RA. We identify the FA-metabolizing enzyme, formyl tetrahydrofolate dehydroge