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

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.

Pubmed ID: 23267094


  • Momb J
  • Lewandowski JP
  • Bryant JD
  • Fitch R
  • Surman DR
  • Vokes SA
  • Appling DR


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

January 8, 2013

Associated Grants

  • Agency: NICHD NIH HHS, Id: F32 HD074428
  • Agency: NIGMS NIH HHS, Id: GM086856

Mesh Terms

  • Abnormalities, Multiple
  • Aminohydrolases
  • Animals
  • Craniofacial Abnormalities
  • DNA Primers
  • Embryonic Development
  • Formate-Tetrahydrofolate Ligase
  • Formates
  • Gene Deletion
  • Genotype
  • Immunoblotting
  • Metabolic Networks and Pathways
  • Methylenetetrahydrofolate Dehydrogenase (NADP)
  • Mice
  • Mice, Knockout
  • Multienzyme Complexes
  • Neural Tube Defects
  • Reverse Transcriptase Polymerase Chain Reaction