Biology subjects

Fainsod, A.

Publications and source records attributed to Fainsod, A..

3 recordsLinked to original sources

bioRxiv2025

ALDH1L1 links folic acid and retinoic acid to prevent neural tube defects

Folic acid (FA) supplementation during pregnancy is the commonly accepted treatment to prevent neurodevelopmental defects. The mechanism by which FA prevents neural tube defects (NTDs) remains unclear. FA also prevents other developmental malformations, including the alcohol-induced malformations in Fetal Alcohol Syndrome models. We show that FA acts through a metabolic link to retinoic acid (RA) signaling. Using a pax3-knockdown Xenopus model of FA-rescueable NTDs, we show that RA or its precursors equally rescue these defects. Similarly, FA rescues alcohol-induced NTDs in a model previously shown to be rescued by RA. We identify the FA-metabolizing enzyme, formyl tetrahydrofolate dehydrogenase (ALDH1L1, FTHFD), encoded by the aldh1l1 gene, as essential for this rescue. Mechanistically, FA upregulates aldh1l1 expression, leading to increased RA biosynthesis. Knockdown of the ALDH1L1 activity using CRISPR/Cas9 abolishes the FA protective effect. To support these observations, we show that the human ALDH1L1 enzyme converts retinaldehyde to RA, and its overexpression restores neural tube closure in aldh1l1-knockdown embryos when retinaldehyde is provided. At the cellular level, reduced RA signaling induces an overproliferation of neural plate precursors and a pathological expansion of the neural tube. ALDH1L1 enables FA to restore normal neural plate proliferation, thereby preventing NTDs. These findings establish ALDH1L1 as a previously unrecognized enzymatic link between FA (vitamin B9) and RA signaling, revealing how FA supplementation safeguards neural development and suggesting opportunities to refine strategies for NTD prevention. Significance StatementDespite the global success of folic acid (FA) supplementation in preventing neural tube defects (NTDs), the medical community continues to debate its exact mechanism, optimal dosage, and why it fails in some cases. This study provides a breakthrough by providing a mechanistic explanation linking FA supplementation and retinoic acid (RA) signaling. We identify the enzyme ALDH1L1 as the molecular bridge between FA and RA and demonstrate that FA protection is indirect, requiring ALDH1L1 to convert Vitamin A into RA. This discovery reframes the debate surrounding FA in the prevention of NTDs. Clinically, our findings suggest that integrating FA supplementation with optimized Vitamin A levels could improve current preventive practices and maximize neurodevelopmental safeguards during early pregnancy.

developmental biology↗

bioRxiv2022

Enhanced loss of retinoic acid network genes in Xenopus laevis achieves a tighter signal regulation

Retinoic acid (RA) is a major regulatory signal during embryogenesis produced from vitamin A (retinol) by an extensive, autoregulating metabolic and signaling network to prevent fluctuations that result in developmental malformations. Xenopus laevis is an allotetraploid hybrid frog species whose genome includes L (long) and S (short) chromosomes from the originating species. Evolutionarily, the X. laevis subgenomes have been losing either L or S homoeologs in about 43% of genes to generate singletons. In the RA network, out of the 47 genes, about 46% have lost one of the homoeologs, like the genome average. In contrast, RA metabolism genes from storage (retinyl esters) to retinaldehyde production exhibit enhanced gene loss with 75% singletons out of 28 genes. The effect of this gene loss on RA signaling autoregulation was studied. Employing transient RA manipulations, homoeolog gene pairs were identified in which one homeolog exhibits enhanced responses or looser regulation than the other, while in other pairs both homoeologs exhibit similar RA responses. CRISPR /Cas9 targeting of individual homoeologs to reduce their activity supports the hypothesis where the RA metabolic network gene loss results in tighter network regulation and more efficient RA robustness responses to overcome complex regulation conditions.

molecular biology↗

bioRxiv2020

Asymmetric robustness in the feedback control of the retinoic acid network response to environmental disturbances

Robustness is a feature of regulatory pathways to ensure signal consistency in light of environmental changes or genetic polymorphisms. The retinoic acid (RA) pathway, is a central developmental and tissue homeostasis regulatory signal, strongly dependent on nutritional sources of retinoids and affected by environmental chemicals. This pathway is characterized by multiple proteins or enzymes capable of performing each step and their integration into a self-regulating network. We studied RA network robustness by transient physiological RA signaling disturbances followed by kinetic transcriptomic analysis of the recovery during embryogenesis. The RA metabolic network was identified as the main regulated module to achieve signaling robustness using an unbiased pattern analysis. We describe the network-wide responses to RA signal manipulation and found the feedback autoregulation to be sensitive to the direction of the RA perturbation: RA knockdown exhibited an upper response limit, whereas RA addition had a minimal feedback-activation threshold. Surprisingly, our robustness response analysis suggests that the RA metabolic network regulation exhibits a multi-objective optimization, known as Pareto optimization, characterized by trade-offs between competing functionalities. We observe that efficient robustness to increasing RA is accompanied by worsening robustness to reduced RA levels and vice versa. This direction-dependent trade-off in the network-wide feedback response, results in an uneven robustness capacity of the RA network during early embryogenesis, likely a significant contributor to the manifestation of developmental defects.

developmental biology↗