ALDH1L1 links folic acid and retinoic acid to prevent neural tube defects

Folic acid (FA) supplementation is a cornerstone of pregnancy care 1, yet the mechanism by which it prevents neural tube defects (NTDs) remains unclear. FA also prevents other developmental malformations, including several alcohol-induced malformations in Fetal Alcohol Syndrome (FAS) models 2-9. Here, we show that FA acts through a direct metabolic link with retinoic acid (RA) synthesis. Using a pax3-knockdown Xenopus model of FA-rescueable NTDs 10, 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 11. We identify the FA-metabolizing enzyme, formyl tetrahydrofolate dehydrogenase, encoded by the aldh1l1 gene 12, as essential for this rescue: FA upregulates aldh1l1 expression and RA biosynthesis, and loss of aldh1l1 abolishes the FA protective effect. Remarkably, human ALDH1L1 converts retinaldehyde to RA, and its overexpression restores neural tube closure in aldh1l1-knockdown embryos when retinaldehyde is provided. ALDH1L1 enables FA to restore normal proliferation of neural plate precursors, thereby preventing pathological expansion. These findings establish ALDH1L1 as a previously unrecognized enzymatic link between vitamin B9 and retinoic acid signaling, revealing how FA supplementation safeguards neural development and suggesting opportunities to refine preventive strategies for NTDs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/681787v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1e5e064org.highwire.dtl.DTLVardef@eeec29org.highwire.dtl.DTLVardef@1d2a976org.highwire.dtl.DTLVardef@173b633_HPS_FORMAT_FIGEXP M_FIG C_FIG