{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:19:25Z","timestamp":1791285565944,"version":"4.1.0"},"reference-count":86,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2008,3,28]],"date-time":"2008-03-28T00:00:00Z","timestamp":1206662400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2008,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:bold>BACKGROUND:<\/jats:bold> The reduced folate carrier (<jats:italic>RFC1<\/jats:italic>) is a ubiquitously expressed integral membrane protein that mediates delivery of 5\u2010methyltetrahydrofolate into mammalian cells. In this study, embryonic\/fetal development is characterized in an <jats:italic>RFC1<\/jats:italic> knockout mouse model in which pregnant dams receive different levels of folate supplementation. <jats:bold>METHODS:<\/jats:bold> <jats:italic>RFC1<jats:sup>+\/\u2212<\/jats:sup><\/jats:italic> males were mated to <jats:italic>RFC1<jats:sup>+\/\u2212<\/jats:sup><\/jats:italic> females, and pregnant dams were treated with vehicle (control) or folic acid (25 or 50 mg\/kg) by daily subcutaneous injection (0.1 mL\/10 g bwt), beginning on E0.5 and continuing throughout gestation until the time of sacrifice. <jats:bold>RESULTS:<\/jats:bold> Without maternal folate supplementation, <jats:italic>RFC1<\/jats:italic> nullizygous embryos die shortly postimplantation. Supplementation of pregnant dams with 25 mg\/kg\/day folic acid prolongs survival of mutant embryos until E9.5\u2013E10.5, but they are developmentally delayed relative to wild\u2010type littermates, display a marked absence of erythropoiesis, severe neural tube and limb bud defects, and failure of chorioallantoic fusion. Fgfr2 protein levels are significantly reduced or absent in the extraembryonic membranes of <jats:italic>RFC1<\/jats:italic> nullizygous embryos. Maternal folate supplementation with 50 mg\/kg\/day results in survival of 22% of <jats:italic>RFC1<\/jats:italic> mutants to E18.5, but they develop with multiple malformations of the eyelids, lungs, heart, and skin. <jats:bold>CONCLUSIONS:<\/jats:bold> High doses of daily maternal folate supplementation during embryonic\/fetal development are necessary for early postimplantation embryonic viability of <jats:italic>RFC1<\/jats:italic> nullizygous embryos, and play a critical role in chorioallantoic fusion, erythropoiesis, and proper development of the neural tube, limbs, lungs, heart, and skin. Birth Defects Research (Part A), 2008. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/bdra.20453","type":"journal-article","created":{"date-parts":[[2008,3,29]],"date-time":"2008-03-29T03:10:38Z","timestamp":1206760238000},"page":"494-507","source":"Crossref","is-referenced-by-count":66,"title":["Embryonic development in the reduced folate carrier knockout mouse is modulated by maternal folate supplementation"],"prefix":"10.1002","volume":"82","author":[{"given":"Janee","family":"Gelineau\u2010van Waes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Heller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda K.","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Wilberding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce R.","family":"Maddox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Aleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"Rosenquist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard H.","family":"Finnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,7,22]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/77076"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.9.5082"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.21.11895"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.1998.2772"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1089\/152581601753193797"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1050-1738(01)00080-9"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00206.2000"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2005.04857.x"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.14.1.111"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.6.686"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm778"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrc.10025"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001703-199504000-00003"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199212243272602"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2006.07.001"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2001-19739"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.127.3.483"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0070-2153(08)60451-2"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.121.2.407"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2004.01.001"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M300079-MCP200"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0631608100"},{"key":"e_1_2_6_24_1","first-page":"497","volume-title":"Chemistry and Biology of Pteridines and Folates","author":"Gelineau\u2010van Waes J","year":"2007"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.1.1"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00429-004-0412-3"},{"key":"e_1_2_6_27_1","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1242\/dev.126.6.1247","article-title":"Mrj encodes a DnaJ\u2010related co\u2010chaperone that is essential for murine placental development","volume":"126","author":"Hunter PJ","year":"1999","journal-title":"Development"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9926(200102)63:2<79::AID-TERA1013>3.0.CO;2-3"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(01)00040-5"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.121.2.489"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90030-2"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/82609"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.1205"},{"key":"e_1_2_6_34_1","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1158\/0008-5472.887.65.3","article-title":"Folate transport gene inactivation in mice increases sensitivity to colon carcinogenesis","volume":"65","author":"Ma DW","year":"2005","journal-title":"Cancer Res"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-213X-3-6"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0959-8049(94)90257-7"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.03.021"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0083-6729(03)01012-4"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.10458"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2001.0409"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.moh.0000219654.65538.5b"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.16.8612"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.21.1.407"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1970.tb01443.x"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.5A6899.2006"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(91)90133-A"},{"key":"e_1_2_6_47_1","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1242\/dev.125.9.1747","article-title":"Progressive lineage analysis by cell sorting and culture identifies FLK1\u2010VE\u2010cadherin+ cells at a diverging point of endothelial and hemopoietic lineages","volume":"125","author":"Nishikawa SI","year":"1998","journal-title":"Development"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90391-3"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrd.1080390113"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2001-2-3-reviews3005"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2002.0730"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1993.1116"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V86.1.156.bloodjournal861156"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02367"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2001.0373"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annepidem.2005.02.014"},{"key":"e_1_2_6_57_1","first-page":"341","article-title":"[Epidemiological study on reduced folate carrier gene (RFC1 A80G) polymorphism and other risk factors of neural tube defects]","volume":"37","author":"Pei LJ","year":"2005","journal-title":"Beijing Da Xue Xue Bao"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/13861"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-16-06125.2000"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.10203"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001648-199801000-00019"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420490210"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.10195"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320590428"},{"key":"e_1_2_6_65_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001648-199505000-00005"},{"key":"e_1_2_6_66_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwg189"},{"key":"e_1_2_6_67_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.19.1.91"},{"key":"e_1_2_6_68_1","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1242\/dev.126.8.1753","article-title":"Early embryonic lethality in Bmp5;Bmp7 double mutant mice suggests functional redundancy within the 60A subgroup","volume":"126","author":"Solloway MJ","year":"1999","journal-title":"Development"},{"key":"e_1_2_6_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.20107"},{"key":"e_1_2_6_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30053"},{"key":"e_1_2_6_71_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20043"},{"key":"e_1_2_6_72_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01892"},{"key":"e_1_2_6_73_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02365"},{"key":"e_1_2_6_74_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420510205"},{"key":"e_1_2_6_75_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.128.16.3179"},{"key":"e_1_2_6_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0005-2736(01)00340-6"},{"key":"e_1_2_6_77_1","first-page":"6708","article-title":"Cellular localization of the folate receptor: potential role in drug toxicity and folate homeostasis","volume":"52","author":"Weitman SD","year":"1992","journal-title":"Cancer Res"},{"key":"e_1_2_6_78_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1993.03500100055027"},{"key":"e_1_2_6_79_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02313"},{"key":"e_1_2_6_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2005.02.027"},{"key":"e_1_2_6_81_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.125.4.753"},{"key":"e_1_2_6_82_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.121.2.549"},{"key":"e_1_2_6_83_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.1987.tb02809.x"},{"key":"e_1_2_6_84_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000136815.73623.BE"},{"key":"e_1_2_6_85_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0796-275"},{"key":"e_1_2_6_86_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C000905200"},{"key":"e_1_2_6_87_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20347"}],"container-title":["Birth Defects Research Part A: Clinical and Molecular Teratology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fbdra.20453","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bdra.20453","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T20:51:01Z","timestamp":1699995061000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/bdra.20453"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,7]]},"references-count":86,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2008,7]]}},"alternative-id":["10.1002\/bdra.20453"],"URL":"https:\/\/doi.org\/10.1002\/bdra.20453","archive":["Portico"],"relation":{},"ISSN":["1542-0752","1542-0760"],"issn-type":[{"value":"1542-0752","type":"print"},{"value":"1542-0760","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,7]]}}}