{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T08:16:23Z","timestamp":1793520983614,"version":"4.5.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"2","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,1,8]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>Mthfd1l<\/jats:italic>\n                    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\n                    <jats:italic>Mthfd1l<\/jats:italic>\n                    knockout mice. All embryos lacking\n                    <jats:italic>Mthfd1l<\/jats:italic>\n                    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\n                    <jats:italic>Mthfd1l<\/jats:italic>\n                    . 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\n                    <jats:italic>MTHFD1L<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1211199110","type":"journal-article","created":{"date-parts":[[2012,12,24]],"date-time":"2012-12-24T23:14:38Z","timestamp":1356390878000},"page":"549-554","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":157,"title":["Deletion of\n                    <i>Mthfd1l<\/i>\n                    causes embryonic lethality and neural tube and craniofacial defects in mice"],"prefix":"10.1073","volume":"110","author":[{"given":"Jessica","family":"Momb","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan P.","family":"Lewandowski","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Biology,"},{"name":"Section of Molecular Cell and Developmental Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Bryant","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Fitch","sequence":"additional","affiliation":[{"name":"Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX 78712"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah R.","family":"Surman","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Vokes","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Biology,"},{"name":"Section of Molecular Cell and Developmental Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean R.","family":"Appling","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry,"},{"name":"Institute for Cellular and Molecular Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,12,24]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(65)91895-7"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/wsbm.72"},{"key":"e_1_3_3_3_2","first-page":"133","volume-title":"Folate in Health and Disease","author":"Hobbs CA","year":"2010","unstructured":"CA Hobbs, GM Shaw, MM Werler, B Mosley, Folate status and birth defect risk. Epidemiological perspective. Folate in Health and Disease, ed LB Bailey (CRC Press, Taylor & Francis Group, 2nd ed, Boca Raton, FL), pp. 133\u2013153 (2010).","edition":"2"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.012809.104810"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(88)81040-4"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)38612-X"},{"key":"e_1_3_3_7_2","first-page":"171","article-title":"In vitro evidence for the involvement of mitochondrial folate metabolism in the supply of cytoplasmic one-carbon units","volume":"1","author":"Barlowe CK","year":"1988","unstructured":"CK Barlowe, DR Appling, In vitro evidence for the involvement of mitochondrial folate metabolism in the supply of cytoplasmic one-carbon units. 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