Nature Genetics
23, 228 - 232 (1999)
doi:10.1038/13861
Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic developmentJorge A. Piedrahita1, 2, Betty Oetama1, 2, Gregory D. Bennett1, 2, 7, Janée van Waes1, 2, 7, Barton A. Kamen4, James Richardson5, Stephen W. Lacey6, Richard G.W. Anderson3
& Richard H. Finnell1, 2, 71
Department of Veterinary Anatomy and Public Health, Texas A&M University, College Station, Texas 77843-4458, USA. 2
Center for Environmental and Rural Health, Texas A&M University, College Station, Texas 77843-4458, USA. 3
Department of Cell Biology, UT-Southwestern Medical Center, Dallas, Texas 75235, USA. 4
Departments of Pharmacology and Pediatrics, UT-Southwestern Medical Center, Dallas, Texas 75235, USA. 5
Department of Pathology, UT-Southwestern Medical Center, Dallas, Texas 75235, USA. 6
Division of Gastroenterology, UT-Southwestern Medical Center, Dallas, Texas 75235, USA. 7
Center for Human Molecular Genetics, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Correspondence should be addressed to Richard H. Finnell rfinnell@unmc.eduPericonceptional folic acid supplementation reduces the occurrence of several human congenital malformations, including craniofacial, heart and neural tube defects1,
2,
3,
4. Although the underlying mechanism is unknown, there may be a maternal-to-fetal folate-transport defect or an inherent fetal biochemical disorder that is neutralized by supplementation. Previous experiments have identified a folate-binding protein5,
6,
7 (Folbp1) that functions as a membrane receptor to mediate the high-affinity internalization and delivery of folate to the cytoplasm of the cell8,
9,
10. In vitro, this receptor facilitates the accumulation of cellular folate a thousand-fold relative to the media, suggesting that it may be essential in cytoplasmic folate delivery in vivo. The importance of an adequate intracellular folate pool for normal embryogenesis has long been recognized in humans11,
12,
13,
14,
15,
16 and experimental animals17,
18,
19. To determine whether Folbp1 is involved in maternal-to-fetal folate transport, we inactivated Folbp1 in mice. We also produced mice lacking Folbp2, another member of the folate receptor family that is GPI anchored but binds folate poorly20. Folbp2−/− embryos developed normally, but Folbp1−/− embryos had severe morphogenetic abnormalities and died in utero by embryonic day (E) 10. Supplementing pregnant Folbp1+/− dams with folinic acid reversed this phenotype in nullizygous pups. Our results suggest that Folbp1 has a critical role in folate homeostasis during development, and that functional defects in the human homologue (FOLR1) of Folbp1 may contribute to similar defects in humans.
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