Deletion of Mthfd1/ causes embryonic lethality and neural tube and craniofacial defects in mice

摘要

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 Mthfd1/ gene encodes a mito-chondrial 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 MthfdH knockout mice. All embryos lacking Mthfdil 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-def icient diet to cause this phenotype. Maternal supplementation with sodium formate decreases the incidence of NTDs and partially rescues the growth defect in embryos lacking Mthfdil. These results reveal the critical role of mitochond-rially 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.%Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, TX 78712;rnInstitute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712,Section of Molecular Cell and Developmental Biology, The University of Texas at Austin, Austin, TX 78712;rnDepartment of Chemistry and Biochemistry, The University of Texas at Austin, Austin, TX 78712;rnDell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78712;rnInstitute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;rnInstitute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712,Section of Molecular Cell and Developmental Biology, The University of Texas at Austin, Austin, TX 78712;Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, TX 78712,Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;