Cardiovascular abnormalities in Folr1 knockout mice and folate rescue

Huiping Zhu, Bogdan J. Wlodarczyk, Melissa Scott, Wei Yu, Michelle Merriweather, Janee Gelineau-van Waes, Robert J. Schwartz, Richard H. Finnell

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

BACKGROUND: Periconceptional folic acid supplementation is widely believed to aid in the prevention of neural tube defects (NTDs), orofacial clefts, and congenital heart defects. Folate-binding proteins or receptors serve to bind folic acid and 5-methyltetrahydrofolate, representing one of the two major mechanisms of cellular folate uptake. METHODS: We herein describe abnormal cardiovascular development in mouse fetuses lacking a functional folate-binding protein gene (Folr1). We also performed a dose-response study with folinic acid and determined the impact of maternal folate supplementation on Folr1 nullizygous cardiac development. RESULTS: Partially rescued preterm Folr1 -/- (formerly referred to as Folbp1) fetuses were found to have outflow tract defects, aortic arch artery abnormalities, and isolated dextracardia. Maternal supplementation with folinic acid rescued the embryonic lethality and the observed cardiovascular phenotypes in a dose-dependant manner. Maternal genotype exhibited significant impact on the rescue efficiency, suggesting an important role of in utero folate status in embryonic development. Abnormal heart looping was observed during early development of Folr1 -/- embryos partially rescued by maternal folinic acid supplementation. Migration pattern of cardiac neural crest cells, genetic signals in pharyngeal arches, and the secondary heart field were also found to be affected in the mutant embryos. CONCLUSIONS: Our observations suggest that the beneficial effect of folic acid for congenital heart defects might be mediated via its impact on neural crest cells and by gene regulation of signaling pathways involved in the development of the pharyngeal arches and the secondary heart field.

Original languageEnglish
Pages (from-to)257-268
Number of pages12
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Volume79
Issue number4
DOIs
StatePublished - Apr 2007
Externally publishedYes

Fingerprint

Cardiovascular Abnormalities
Folic Acid
Knockout Mice
Leucovorin
Mothers
Branchial Region
Congenital Heart Defects
Neural Crest
Embryonic Development
Carrier Proteins
Fetus
Neural Tube Defects
Thoracic Aorta
Genes
Embryonic Structures
Arteries
Genotype
Phenotype

All Science Journal Classification (ASJC) codes

  • Developmental Biology

Cite this

Cardiovascular abnormalities in Folr1 knockout mice and folate rescue. / Zhu, Huiping; Wlodarczyk, Bogdan J.; Scott, Melissa; Yu, Wei; Merriweather, Michelle; Gelineau-van Waes, Janee; Schwartz, Robert J.; Finnell, Richard H.

In: Birth Defects Research Part A - Clinical and Molecular Teratology, Vol. 79, No. 4, 04.2007, p. 257-268.

Research output: Contribution to journalArticle

Zhu, Huiping ; Wlodarczyk, Bogdan J. ; Scott, Melissa ; Yu, Wei ; Merriweather, Michelle ; Gelineau-van Waes, Janee ; Schwartz, Robert J. ; Finnell, Richard H. / Cardiovascular abnormalities in Folr1 knockout mice and folate rescue. In: Birth Defects Research Part A - Clinical and Molecular Teratology. 2007 ; Vol. 79, No. 4. pp. 257-268.
@article{50b8a52561e342fdb7c4846fd6030514,
title = "Cardiovascular abnormalities in Folr1 knockout mice and folate rescue",
abstract = "BACKGROUND: Periconceptional folic acid supplementation is widely believed to aid in the prevention of neural tube defects (NTDs), orofacial clefts, and congenital heart defects. Folate-binding proteins or receptors serve to bind folic acid and 5-methyltetrahydrofolate, representing one of the two major mechanisms of cellular folate uptake. METHODS: We herein describe abnormal cardiovascular development in mouse fetuses lacking a functional folate-binding protein gene (Folr1). We also performed a dose-response study with folinic acid and determined the impact of maternal folate supplementation on Folr1 nullizygous cardiac development. RESULTS: Partially rescued preterm Folr1 -/- (formerly referred to as Folbp1) fetuses were found to have outflow tract defects, aortic arch artery abnormalities, and isolated dextracardia. Maternal supplementation with folinic acid rescued the embryonic lethality and the observed cardiovascular phenotypes in a dose-dependant manner. Maternal genotype exhibited significant impact on the rescue efficiency, suggesting an important role of in utero folate status in embryonic development. Abnormal heart looping was observed during early development of Folr1 -/- embryos partially rescued by maternal folinic acid supplementation. Migration pattern of cardiac neural crest cells, genetic signals in pharyngeal arches, and the secondary heart field were also found to be affected in the mutant embryos. CONCLUSIONS: Our observations suggest that the beneficial effect of folic acid for congenital heart defects might be mediated via its impact on neural crest cells and by gene regulation of signaling pathways involved in the development of the pharyngeal arches and the secondary heart field.",
author = "Huiping Zhu and Wlodarczyk, {Bogdan J.} and Melissa Scott and Wei Yu and Michelle Merriweather and {Gelineau-van Waes}, Janee and Schwartz, {Robert J.} and Finnell, {Richard H.}",
year = "2007",
month = "4",
doi = "10.1002/bdra.20347",
language = "English",
volume = "79",
pages = "257--268",
journal = "Teratology",
issn = "1542-0752",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - Cardiovascular abnormalities in Folr1 knockout mice and folate rescue

AU - Zhu, Huiping

AU - Wlodarczyk, Bogdan J.

AU - Scott, Melissa

AU - Yu, Wei

AU - Merriweather, Michelle

AU - Gelineau-van Waes, Janee

AU - Schwartz, Robert J.

AU - Finnell, Richard H.

PY - 2007/4

Y1 - 2007/4

N2 - BACKGROUND: Periconceptional folic acid supplementation is widely believed to aid in the prevention of neural tube defects (NTDs), orofacial clefts, and congenital heart defects. Folate-binding proteins or receptors serve to bind folic acid and 5-methyltetrahydrofolate, representing one of the two major mechanisms of cellular folate uptake. METHODS: We herein describe abnormal cardiovascular development in mouse fetuses lacking a functional folate-binding protein gene (Folr1). We also performed a dose-response study with folinic acid and determined the impact of maternal folate supplementation on Folr1 nullizygous cardiac development. RESULTS: Partially rescued preterm Folr1 -/- (formerly referred to as Folbp1) fetuses were found to have outflow tract defects, aortic arch artery abnormalities, and isolated dextracardia. Maternal supplementation with folinic acid rescued the embryonic lethality and the observed cardiovascular phenotypes in a dose-dependant manner. Maternal genotype exhibited significant impact on the rescue efficiency, suggesting an important role of in utero folate status in embryonic development. Abnormal heart looping was observed during early development of Folr1 -/- embryos partially rescued by maternal folinic acid supplementation. Migration pattern of cardiac neural crest cells, genetic signals in pharyngeal arches, and the secondary heart field were also found to be affected in the mutant embryos. CONCLUSIONS: Our observations suggest that the beneficial effect of folic acid for congenital heart defects might be mediated via its impact on neural crest cells and by gene regulation of signaling pathways involved in the development of the pharyngeal arches and the secondary heart field.

AB - BACKGROUND: Periconceptional folic acid supplementation is widely believed to aid in the prevention of neural tube defects (NTDs), orofacial clefts, and congenital heart defects. Folate-binding proteins or receptors serve to bind folic acid and 5-methyltetrahydrofolate, representing one of the two major mechanisms of cellular folate uptake. METHODS: We herein describe abnormal cardiovascular development in mouse fetuses lacking a functional folate-binding protein gene (Folr1). We also performed a dose-response study with folinic acid and determined the impact of maternal folate supplementation on Folr1 nullizygous cardiac development. RESULTS: Partially rescued preterm Folr1 -/- (formerly referred to as Folbp1) fetuses were found to have outflow tract defects, aortic arch artery abnormalities, and isolated dextracardia. Maternal supplementation with folinic acid rescued the embryonic lethality and the observed cardiovascular phenotypes in a dose-dependant manner. Maternal genotype exhibited significant impact on the rescue efficiency, suggesting an important role of in utero folate status in embryonic development. Abnormal heart looping was observed during early development of Folr1 -/- embryos partially rescued by maternal folinic acid supplementation. Migration pattern of cardiac neural crest cells, genetic signals in pharyngeal arches, and the secondary heart field were also found to be affected in the mutant embryos. CONCLUSIONS: Our observations suggest that the beneficial effect of folic acid for congenital heart defects might be mediated via its impact on neural crest cells and by gene regulation of signaling pathways involved in the development of the pharyngeal arches and the secondary heart field.

UR - http://www.scopus.com/inward/record.url?scp=34250827739&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34250827739&partnerID=8YFLogxK

U2 - 10.1002/bdra.20347

DO - 10.1002/bdra.20347

M3 - Article

C2 - 17286298

AN - SCOPUS:34250827739

VL - 79

SP - 257

EP - 268

JO - Teratology

JF - Teratology

SN - 1542-0752

IS - 4

ER -