Researchers at the Hebrew University of Jerusalem have identified a biological mechanism that may help explain how folic acid protects developing embryos against serious birth defects affecting the brain and spinal cord, offering new insight into a longstanding question in prenatal health research.
The study, led by Prof. Abraham Fainsod and M.D./Ph.D. student Tamir Edri of the Hebrew University Faculty of Medicine in collaboration with Prof. José António Belo of NOVA Medical School in Portugal, was published in PNAS. Researchers found evidence that folic acid’s protective effect depends on an enzyme called ALDH1L1, which helps developing embryos produce retinoic acid, a vitamin A-derived signal important to nervous system formation.
Folic Acid’s Role in Neural Tube Development
Folic acid, also known as vitamin B9, has long been used to reduce the risk of neural tube defects. These serious birth defects occur when the early structure that eventually develops into the brain and spinal cord does not close properly.
During early embryonic development, a sheet of cells known as the neural plate begins folding upward. Its edges must eventually come together and close to form the neural tube. Disruptions in this process can result in neural tube defects.
Scientists have known for decades that folic acid can help prevent many of these conditions. However, the precise biological mechanism responsible for that protection has remained less clear.
The new research suggests folic acid helps activate ALDH1L1, a gene responsible for producing the ALDH1L1 enzyme. That enzyme can help convert retinaldehyde, a molecule related to vitamin A, into retinoic acid.
Retinoic acid serves as an important developmental signal, helping regulate when cells grow, what types of cells they become, where they move and when they stop dividing.
ALDH1L1 Appears Critical to Folic Acid’s Protective Effect
Researchers tested the role of ALDH1L1 by studying embryos experiencing neural tube closure problems. When the researchers treated frog embryos with folic acid, many developed more normally.
The scientists then disrupted the ALDH1L1 gene. Once the gene was disrupted, folic acid lost its protective effect, indicating that ALDH1L1 may be an essential component of the biological process through which folic acid supports neural tube development.
The research team also demonstrated that human ALDH1L1 can produce retinoic acid. Evidence that the same biological pathway is active in mammalian cells further strengthened the possibility that the mechanism could have relevance to humans.
However, additional research will be necessary to determine whether the process operates in the same way during human pregnancy.
Retinoic Acid Levels Influence Developing Nervous System Cells
Researchers also examined what happened when retinoic acid signaling was disrupted.
When retinoic acid levels became too low, cells destined to form part of the nervous system multiplied too rapidly. As a result, the neural plate became abnormally enlarged.
Folic acid helped bring cell proliferation closer to normal levels, but researchers found that the effect occurred only when ALDH1L1 remained functional.
The findings suggest that folic acid may do more than provide nutrients during pregnancy. Instead, it may contribute to a broader signaling system responsible for controlling critical stages of embryonic development.
Study Examines Interaction Between Folic Acid and Vitamin A
Because ALDH1L1 uses a vitamin A-derived molecule to produce retinoic acid, researchers also investigated whether folic acid and vitamin A-related compounds might work together.
In embryonic experiments, small amounts of retinol, a form of vitamin A, enhanced the effect of low-dose folic acid.
The finding, however, does not mean pregnant people should begin taking additional vitamin A. Excessive vitamin A can itself cause serious birth defects, and healthy embryonic development requires retinoic acid levels to remain within a carefully controlled range.
The experiments instead provide scientists with additional information about how folate and vitamin A-related biological pathways may interact during nervous system formation.
Findings Could Help Explain Limits of Folic Acid Protection
The discovery could eventually help researchers investigate why folic acid successfully reduces the risk of neural tube defects in many pregnancies but does not prevent every case.
Problems involving the ALDH1L1–retinoic acid pathway could be one potential explanation, according to the research, although substantially more work is needed before scientists can determine its significance in human pregnancy.
The study provides a new framework for understanding a preventive measure that has been widely recommended for decades. Rather than acting alone, folic acid may protect the developing nervous system partly by helping embryos produce appropriate amounts of retinoic acid during critical stages of early development.
