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

Janee Gelineau-van Waes, Steven Heller, Linda K. Bauer, Justin Wilberding, Joyce R. Maddox, Francisco Aleman, Thomas H. Rosenquist, Richard H. Finnell

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)494-507
Number of pages14
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Volume82
Issue number7
DOIs
StatePublished - Jul 2008
Externally publishedYes

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Reduced Folate Carrier Protein
Folic Acid
Knockout Mice
Embryonic Development
Mothers
Embryonic Structures
Embryonic and Fetal Development
Neural Tube
Erythropoiesis
Limb Buds
Extraembryonic Membranes
Lung
Skin
Eyelids
Subcutaneous Injections
Membrane Proteins
Extremities
Pregnancy

All Science Journal Classification (ASJC) codes

  • Developmental Biology

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Embryonic development in the reduced folate carrier knockout mouse is modulated by maternal folate supplementation. / Gelineau-van Waes, Janee; Heller, Steven; Bauer, Linda K.; Wilberding, Justin; Maddox, Joyce R.; Aleman, Francisco; Rosenquist, Thomas H.; Finnell, Richard H.

In: Birth Defects Research Part A - Clinical and Molecular Teratology, Vol. 82, No. 7, 07.2008, p. 494-507.

Research output: Contribution to journalArticle

Gelineau-van Waes, Janee ; Heller, Steven ; Bauer, Linda K. ; Wilberding, Justin ; Maddox, Joyce R. ; Aleman, Francisco ; Rosenquist, Thomas H. ; Finnell, Richard H. / Embryonic development in the reduced folate carrier knockout mouse is modulated by maternal folate supplementation. In: Birth Defects Research Part A - Clinical and Molecular Teratology. 2008 ; Vol. 82, No. 7. pp. 494-507.
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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.",
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AU - Heller, Steven

AU - Bauer, Linda K.

AU - Wilberding, Justin

AU - Maddox, Joyce R.

AU - Aleman, Francisco

AU - Rosenquist, Thomas H.

AU - Finnell, Richard H.

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N2 - 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.

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