Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice

Abstract

Maternal supplementation with folic acid is known to reduce the incidence of neural tube defects (NTDs) by as much as 70%. Despite the strong clinical link between folate and NTDs, the biochemical mechanisms through which folic acid acts during neural tube development remain undefined. The Mthfd1l gene encodes a mitochondrial monofunctional 10-formyl-tetrahydrofolate synthetase, termed MTHFD1L. This gene is expressed in adults and at all stages of mammalian embryogenesis with localized regions of higher expression along the neural tube, developing brain, craniofacial structures, limb buds, and tail bud. In both embryos and adults, MTHFD1L catalyzes the last step in the flow of one-carbon units from mitochondria to cytoplasm, producing formate from 10-formyl-THF. To investigate the role of mitochondrial formate production during embryonic development, we have analyzed Mthfd1l knockout mice. All embryos lacking Mthfd1l exhibit aberrant neural tube closure including craniorachischisis and exencephaly and/or a wavy neural tube. This fully penetrant folate-pathway mouse model does not require feeding a folate-deficient diet to cause this phenotype. Maternal supplementation with sodium formate decreases the incidence of NTDs and partially rescues the growth defect in embryos lacking Mthfd1l . These results reveal the critical role of mitochondrially derived formate in mammalian development, providing a mechanistic link between folic acid and NTDs. In light of previous studies linking a common splice variant in the human MTHFD1L gene with increased risk for NTDs, this mouse model provides a powerful system to help elucidate the specific metabolic mechanisms that underlie folate-associated birth defects, including NTDs.

Glutathione metabolism links FOXRED1 to NADH:ubiquinone oxidoreductase (complex I) deficiency: A hypothesis

“…Formate export is essential in embryos, but not in adults (Tibbetts and Appling, 2010). Common single nucleotide variants in the MTHFD1 and MTHFD1L genes affect formate metabolism and are documented risk factors for neural tube defects, intrauterine growth restriction, congenital heart defects and neurodegenerative diseases (Parle-McDermott et al, 2009;Tibbetts and Appling, 2010;Momb et al, 2013).…”

“…Export of mitochondrial formate is critical in mammalian embryonic development (Momb et al, 2013). Mitochondrial formate supplies~90% of one-carbon units incorporated into purines, thymidylate (dTMP) and other methyl groups.…”

Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma

“…Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma Derek growth delay, neural tube and craniofacial abnormalities, and embryonic lethality (12). In humans, MTHFD1L polymorphisms are closely related to neural tube defects, coronary artery disease, and Alzheimer's disease (13)(14)(15).…”

In Vivo Kinetics of Formate Metabolism in Folate-deficient and Folate-replete Rats

“…Monofunctional 10-formyl-THF synthetase (MTHFD1L) is the mitochondrial enzyme responsible for the production of formate. Appling et al (5) have shown that knock-out of Mthfd1l is embryonically lethal, with embryos showing both growth defects and aberrant neural tube closure. Maternal supplementation of the drinking water with formate decreased the incidence of neural tube defects and partially rescued the growth defect (5).…”

“…Appling et al (5) have shown that knock-out of Mthfd1l is embryonically lethal, with embryos showing both growth defects and aberrant neural tube closure. Maternal supplementation of the drinking water with formate decreased the incidence of neural tube defects and partially rescued the growth defect (5). These experiments provide strong evidence for a critical role for mitochondrially derived formate in mammalian development.…”