Embryonic development in the reduced folate carrier knockout mouse is modulated by maternal folate supplementation

Authors

  • Janee Gelineau-van Waes,

    Corresponding author
    1. Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5455
    • Dept. of Genetics, Cell Biology & Anatomy, 985455 Nebraska Medical Center, Omaha, NE 68198-5455
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  • Steven Heller,

    1. Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5455
    Current affiliation:
    1. MVP Laboratories, Omaha, NE 68117
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  • Linda K. Bauer,

    1. Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5455
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  • Justin Wilberding,

    1. Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5455
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  • Joyce R. Maddox,

    1. Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5455
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  • Francisco Aleman,

    1. Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5455
    Current affiliation:
    1. St. Louis University School of Medicine, St. Louis, MO, 63101
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  • Thomas H. Rosenquist,

    1. Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198-5455
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  • Richard H. Finnell

    1. Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030
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  • Portions of the material included in this article were presented at the 2005 Neural Tube Defect Conference (Seabrook Island, South Carolina, September 2005), and the 2006 Annual Meeting of the Teratology Society (Tucson, Arizona, June 2006).

  • The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Abstract

BACKGROUND: The reduced folate carrier (RFC1) is a ubiquitously expressed integral membrane protein that mediates delivery of 5-methyltetrahydrofolate into mammalian cells. In this study, embryonic/fetal development is characterized in an RFC1 knockout mouse model in which pregnant dams receive different levels of folate supplementation. METHODS:RFC1+/− males were mated to RFC1+/− 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. RESULTS: Without maternal folate supplementation, RFC1 nullizygous embryos die shortly postimplantation. Supplementation of pregnant dams with 25 mg/kg/day folic acid prolongs survival of mutant embryos until E9.5–E10.5, but they are developmentally delayed relative to wild-type 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 RFC1 nullizygous embryos. Maternal folate supplementation with 50 mg/kg/day results in survival of 22% of RFC1 mutants to E18.5, but they develop with multiple malformations of the eyelids, lungs, heart, and skin. CONCLUSIONS: High doses of daily maternal folate supplementation during embryonic/fetal development are necessary for early postimplantation embryonic viability of RFC1 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. © 2008 Wiley-Liss, Inc.

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