Researchers at the Hebrew University of Jerusalem have identified a key step in how folic acid protects developing embryos from brain and spinal cord birth defects.
The study, led by Prof. Abraham Fainsod and M.D./Ph.D. student Tamir Edri of the Hebrew University Faculty of Medicine, with Prof. José António Belo of NOVA Medical School in Portugal, appears in the Proceedings of the National Academy of Sciences. It shows that folic acid relies on an enzyme called ALDH1L1 to help the embryo produce retinoic acid, a vitamin A-derived signal essential for proper nervous system formation.
Neural tube defects occur when the early structure that becomes the brain and spinal cord fails to close. Before a recognizable brain or spinal cord exists, a sheet of cells known as the neural plate folds upward. Its edges must meet and seal, much like a zipper. When that process fails, serious birth defects can result.
Folic acid, or vitamin B9, has long been known to lower the risk of these defects. Until now, the precise mechanism remained unclear. The new work indicates that folic acid helps activate the ALDH1L1 gene. The enzyme produced by that gene converts a vitamin A-related molecule called retinaldehyde into retinoic acid. Retinoic acid then acts as a set of instructions, guiding cells on when to grow, what to become, where to migrate, and when to stop dividing.
To test the pathway, the researchers created embryos with neural tube closure problems. Treating them with folic acid allowed many of the frog embryos to develop more normally. When the team disrupted the ALDH1L1 gene, however, folic acid lost its protective effect. Without the enzyme, the vitamin could no longer rescue the developing neural tube.
Further experiments showed that the human version of ALDH1L1 can produce retinoic acid. Evidence also pointed to the same biological pathway operating in mammalian cells, raising the possibility that the mechanism is relevant to human development.
When retinoic acid levels dropped too low, the cells destined to form the nervous system multiplied too rapidly, and the neural plate expanded abnormally. Folic acid helped restore more normal cell growth, but only when ALDH1L1 remained functional.
The findings also suggested that vitamin A and folic acid may interact. In the embryonic experiments, small amounts of retinol, a form of vitamin A, improved the effect of low-dose folic acid. The researchers caution that this does not mean pregnant people should take extra vitamin A. Excess vitamin A itself can cause serious birth defects, and healthy development requires retinoic acid levels to stay within a narrow range.
The discovery offers a new explanation for a decades-old medical recommendation. Folic acid may protect the developing nervous system in part by helping the embryo generate the right amount of another crucial signal at the right time. It may also help explain why folic acid prevents many, but not all, neural tube defects. Problems in the ALDH1L1–retinoic acid pathway could be one contributing factor, though more research is needed to confirm whether the same mechanism operates in human pregnancy.
The paper, titled “Folic acid prevention of neural tube defects requires retinoic acid produced by ALDH1L1,” was published in PNAS (2026; 123(31): e2616501123).
