Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development

Jorge A. Piedrahita, Betty Oetama, Gregory D. Bennett, Janée Van Waes, Barton A. Kamen, James Richardson, Stephen W. Lacey, Richard G.W. Anderson, Richard H. Finnell

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277 Scopus citations

Abstract

Periconceptional folic acid supplementation reduces the occurrence of several human congenital malformations, including craniofacial, heart and neural tube defects. 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 protein (Folbp1) that functions as a membrane receptor to mediate the high-affinity internalization and delivery of folate to the cytoplasm of the cell. 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 humans and experimental animals. 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 poorly. 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.

Original languageEnglish (US)
Pages (from-to)228-232
Number of pages5
JournalNature genetics
Volume23
Issue number2
DOIs
StatePublished - Oct 1 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics

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    Piedrahita, J. A., Oetama, B., Bennett, G. D., Van Waes, J., Kamen, B. A., Richardson, J., Lacey, S. W., Anderson, R. G. W., & Finnell, R. H. (1999). Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. Nature genetics, 23(2), 228-232. https://doi.org/10.1038/13861