Researchers at the Hebrew University of Jerusalem and NOVA University Lisbon have identified a molecular pathway that may explain how folic acid (vitamin B9) helps prevent neural tube defects. Their findings link folic acid to retinoic acid, a critical developmental signal produced from vitamin A.
Folic acid supplementation during pregnancy is widely recommended to help prevent neural tube defects.
“Before the fetus develops a recognizable brain or spinal cord, a sheet of cells called the neural plate begins folding upward,” said doctoral student Tamir Edri and his colleagues.
“To form the neural tube, the edges of this structure must meet and close, much like a zipper. When this process fails, a neural tube defect can develop.”
Scientists have known for decades that folic acid can reduce the risk of many neural tube defects. However, the new study suggests that vitamin B9 may do more than provide essential nutrients: It may also activate a key developmental pathway.
The researchers found that folic acid helps activate ALDH1L1, the gene responsible for producing the ALDH1L1 enzyme.
“The ALDH1L1 enzyme may help convert a vitamin A-related molecule called retinaldehyde into retinoic acid,” the researchers said.
Retinoic acid functions as a developmental signal, providing cells with instructions about when to grow, what type of cell to become, where to move, and when to stop dividing.
To determine whether ALDH1L1 plays a central role in neural tube development, the researchers studied frog embryos, a widely used model for investigating early embryonic development.
They generated embryos with neural tube closure problems and treated them with folic acid. In many cases, the vitamin helped the embryos develop more normally.
However, when the researchers disrupted the ALDH1L1 gene, folic acid no longer provided the same protective effect.
These results suggested that ALDH1L1 is necessary for folic acid to rescue neural tube development. Without the enzyme, folic acid was unable to correct the closure defects.
The scientists then demonstrated that human ALDH1L1 can produce retinoic acid. They also found evidence that the same biological pathway is active in mammalian cells, strengthening the possibility that the mechanism may be relevant to human development.
Edri and his coauthors also examined what happens when retinoic acid signaling is disrupted.
“When retinoic acid levels are too low, cells destined to become part of the nervous system grow too quickly, causing the neural plate to become abnormally enlarged,” the researchers said. “Folic acid helped restore normal cell growth, but only when ALDH1L1 was functioning.”
Because ALDH1L1 uses vitamin A-derived molecules to produce retinoic acid, the researchers also investigated whether vitamin A and folic acid could work together.
In embryo experiments, small amounts of retinol, a form of vitamin A, enhanced the effects of low doses of folic acid.
However, the researchers emphasized that these findings do not mean pregnant women should take additional vitamin A without medical advice.
Excess vitamin A can cause serious birth defects, and healthy embryonic development depends on maintaining retinoic acid levels within a narrow range.
“This discovery offers a new way to understand a question that scientists have studied for decades,” the researchers said.
“Folic acid may not protect the developing nervous system by acting alone. Instead, it may work partly by helping the embryo produce the correct amount of another important developmental signal at the right time.”
The findings may also help explain why folic acid prevents many, but not all, neural tube defects.
“Problems involving the ALDH1L1-retinoic acid pathway could be one possible reason,” the researchers said. “However, additional research is needed to determine whether the same mechanism operates during human pregnancy.”
The team’s paper was published on July 30, 2026, in Proceedings of the National Academy of Sciences.
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Tamir Edri et al. 2026. Prevention of neural tube defects by folic acid requires retinoic acid produced by ALDH1L1. PNAS 123 (31): e2616501123; doi: 10.1073/pnas.2616501123
Source: www.sci.news