Researchers at the Hebrew University of Jerusalem have uncovered the molecular mechanism by which folic acid helps prevent serious birth defects of the brain and spinal cord.
In a study led by Professor Abraham Fainsod and his MD student Tamir Edri of the Hebrew University Faculty of Medicine, working with Professor José António Belo of NOVA Medical School in Portugal, scientists showed that folic acid depends on an enzyme called ALDH1L1 to protect the developing nervous system. The findings appear in the journal PNAS.
Folic acid, also known as vitamin B9, is long established as a way to lower the risk of neural tube defects, which occur when the early structure that becomes the brain and spinal cord fails to close properly. Early in development, before an embryo has a recognisable brain or spinal cord, a sheet of cells known as the neural plate begins to fold upwards. Its edges must meet and seal, much like a zip, to form the neural tube, and any failure in this process can lead to neural tube defects. Until now, the precise way folic acid achieves this protection has remained unclear.
The new research indicates the vitamin does more than simply provide nutrients. It helps switch on the ALDH1L1 gene, which produces the ALDH1L1 enzyme. That enzyme converts a vitamin A-related molecule called retinaldehyde into retinoic acid, which functions as a set of instructions directing developing cells on when to grow, what to become, where to move, and when to stop dividing.
To test the importance of ALDH1L1, the researchers generated embryos with neural tube closure problems and treated them with folic acid. The treatment helped many of the frog embryos develop more normally. When the team then disrupted the ALDH1L1 gene, folic acid lost its protective effect and could no longer rescue the developing neural tube.
Further experiments demonstrated that human ALDH1L1 can produce retinoic acid, and that the same biological pathway is active in mammalian cells, supporting the possibility that the mechanism may apply to humans.
The team also examined what happens when the signalling system fails. When retinoic acid levels drop too low, cells destined to form the nervous system multiply too rapidly, and the neural plate expands abnormally. Folic acid restored more normal cell growth, but only when ALDH1L1 remained functional.
The discovery offers a new perspective on a decades-old question, suggesting folic acid may protect the developing nervous system not by acting alone but by helping the embryo generate the right amount of another critical developmental signal at the right time. The results may also help explain why folic acid succeeds in many pregnancies yet does not prevent every neural tube defect: problems in the ALDH1L1 retinoic acid pathway could be one possible reason, though far more research is needed to confirm whether the same mechanism operates in human pregnancy.
The work strengthens understanding of how a simple vitamin supplement safeguards early neural development and points towards refined approaches for preventing these birth defects in future.