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).
Article first published online: 28 MAR 2008
Copyright © 2008 Wiley-Liss, Inc.
Birth Defects Research Part A: Clinical and Molecular Teratology
Volume 82, Issue 7, pages 494–507, July 2008
How to Cite
Gelineau-van Waes, J., Heller, S., Bauer, L. K., Wilberding, J., Maddox, J. R., Aleman, F., Rosenquist, T. H. and Finnell, R. H. (2008), Embryonic development in the reduced folate carrier knockout mouse is modulated by maternal folate supplementation. Birth Defects Research Part A: Clinical and Molecular Teratology, 82: 494–507. doi: 10.1002/bdra.20453
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
- Issue published online: 22 JUL 2008
- Article first published online: 28 MAR 2008
- Manuscript Accepted: 3 FEB 2008
- Manuscript Revised: 31 JAN 2008
- Manuscript Received: 18 OCT 2007
- NHLBI. Grant Number: 1PO1HL66398
- reduced folate carrier knockout;
- maternal folate supplementation;
- chorioallantoic fusion;
- neural tube defect;
- heart defects;
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.