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

For over three decades, one consistent piece of pregnancy guidance has been: consume folic acid. This B-vitamin is known to diminish the risk of neural tube defects, major birth anomalies arising when the initial structure forming the brain and spinal cord fails to close correctly. However, the precise mechanism behind folic acid's protective effect has remained elusive.

Recently, researchers may have uncovered a key element of this enigma. A study published in the Proceedings of the National Academy of Sciences reveals that folic acid works in conjunction with an enzyme known as ALDH1L1. This enzyme contributes to the production of retinoic acid, a potent developmental signal derived from vitamin A. The study was spearheaded by Prof. Abraham Fainsod and Ph.D. student Tamir Edri from the Hebrew University of Jerusalem's Faculty of Medicine, alongside Prof. José António Belo and an international group of experts.

The research journey commenced at the embryonic stage. Prior to the embryo developing a discernible brain or spinal cord, a cellular layer called the neural plate commences to fold inward. The edges of this structure must converge and fuse, resembling a zipper, to form the neural tube. Malfunctions in this process can lead to neural tube defects.

While it was known that folic acid could prevent many of these defects, its mechanism of action seemed to extend beyond mere nutrient provision. This investigation suggests that folic acid may initiate ALDH1L1, a gene encoding for the ALDH1L1 enzyme. This enzyme subsequently aids in converting a vitamin A-related molecule, retinaldehyde, into retinoic acid.

Retinoic acid functions akin to instructions, guiding the growth, identity, location, and division of developing cells. To ascertain the significance of ALDH1L1, the researchers utilized frog embryos, a standard model for studying early development. They generated embryos with neural tube closure defects and subsequently treated them with folic acid.

Folic acid facilitated the normal development of many of these embryos. However, when the ALDH1L1 gene was disrupted, folic acid's protective effect was rendered ineffective. This finding provided a critical clue: without ALDH1L1, folic acid could no longer safeguard the developing neural tube. The team further corroborated this hypothesis by demonstrating that human ALDH1L1 can synthesize retinoic acid.

They also discovered evidence indicating that this pathway is active in mammalian cells, bolstering the likelihood of its relevance to human health. Moreover, the researchers observed the outcomes of a malfunctioning signaling system. When retinoic acid levels were insufficient, cells destined to become part of the nervous system proliferated excessively, resulting in an abnormally enlarged neural plate.

Folic acid helped rectify this cell growth imbalance—but only when ALDH1L1 was functional. These results also hinted at another possibility. Since ALDH1L1 utilizes a vitamin A-derived molecule to generate retinoic acid, the researchers investigated whether vitamin A and folic acid might synergize. In their embryonic experiments, minute quantities of retinol, a form of vitamin A, augmented the effectiveness of low-dose folic acid.

However, this does not imply that pregnant individuals should initiate extra vitamin A supplementation. The study cautions that excessive vitamin A can induce severe birth defects, and optimal development necessitates maintaining retinoic acid levels within a precise range. Instead, this discovery offers scientists a novel perspective on a longstanding query.

Folic acid might not safeguard the developing nervous system solely; it may function in part by facilitating the embryo's production of an adequate amount of another essential developmental signal at the appropriate time. This finding could also elucidate why folic acid is effective in numerous pregnancies but fails to prevent all neural tube defects.

The authors posit that issues within the ALDH1L1–retinoic acid pathway could be one potential reason, although further research is required to ascertain whether the same mechanism exists in human pregnancy.