How folic acid may protect a baby’s developing brain and spinal cord

For more than 30 years, one piece of pregnancy advice has been remarkably consistent: Take folic acid. The reason is clear. Folic acid, or vitamin B9, can lower the risk of neural tube defects, serious birth defects that happen when the early structure that becomes the brain and spinal cord does not close properly. What has been much less clear is how folic acid works.

Now, researchers may have found an important part of the answer. In a new study published in the Proceedings of the National Academy of Sciences, scientists discovered that folic acid appears to rely on an enzyme called ALDH1L1. That enzyme helps produce retinoic acid, a powerful developmental signal made from vitamin A.

The study was led by professor Abraham Fainsod and his M.D./Ph.D. student Tamir Edri of the Hebrew University of Jerusalem Faculty of Medicine, with professor José António Belo of NOVA Medical School in Portugal and an international team of researchers.

How the neural tube closes

The story begins very early in development. Before an embryo has a recognizable brain or spinal cord, a sheet of cells called the neural plate begins to fold upward. Its edges must meet and close, almost like a zipper, to make the neural tube. If that process goes wrong, neural tube defects can result.

Scientists have long known that folic acid can help prevent many of these defects. But the vitamin seems to be doing more than simply supplying nutrients.

The new research suggests that folic acid helps switch on ALDH1L1, a gene that makes the ALDH1L1 enzyme. That enzyme can then help turn a vitamin A-related molecule called retinaldehyde into retinoic acid. Retinoic acid acts like a set of instructions, telling developing cells when to grow, what to become, where to go and when to stop dividing.

When folic acid stops working

To test whether ALDH1L1 was truly important, the researchers used frog embryos, a common model for studying early development. They created embryos with neural tube closure problems and then treated them with folic acid.

Folic acid helped many of the embryos develop more normally.

Then the researchers disrupted the ALDH1L1 gene. This time, folic acid lost its protective effect. That result was a major clue: Without ALDH1L1, folic acid could no longer rescue the developing neural tube.

The team pushed the idea further, demonstrating 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 could be relevant to humans.

A narrow window for vitamin A

The researchers also saw what happened when this signaling system broke down.

When retinoic acid levels were too low, the cells that would become part of the nervous system multiplied too quickly. The neural plate became abnormally expanded. Folic acid helped bring that cell growth back toward normal—but only when ALDH1L1 was working.

The findings also raised another possibility. Because ALDH1L1 uses a vitamin A-derived molecule to make retinoic acid, the researchers tested whether vitamin A and folic acid might work together. In their embryo experiments, small amounts of retinol, a form of vitamin A, improved the effect of low-dose folic acid.

That does not mean pregnant people should start taking extra vitamin A. The study warns that too much vitamin A can itself cause serious birth defects, and healthy development depends on keeping retinoic acid levels within a narrow range.

One clue to folic acid’s limits

Instead, the discovery gives scientists a new way to think about a decades-old question. Folic acid may not protect the developing nervous system by acting alone. It may work partly by helping the embryo produce the right amount of another crucial developmental signal at exactly the right time.

The finding could also help explain why folic acid works well in many pregnancies but does not prevent every neural tube defect. The authors say problems in the ALDH1L1–retinoic acid pathway could be one possible reason, although much more research is needed to determine whether the same mechanism operates in human pregnancy.

Who’s behind this story?

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Lisa Lock

BA art history, MA material culture. Former museum editor, paramedic, and transplant coordinator. Editing for Science X since 2021.

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Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

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