Cardiovascular abnormalities in Folr1 knockout mice and folate rescue

Wiley - Tập 79 Số 4 - Trang 257-268 - 2007
Huiping Zhu1,2, Bogdan J. Wlodarczyk1, Melissa Scott1, Wei Yu3, Michelle Merriweather1, Janee Gelineau‐van Waes4, Robert J. Schwartz3, Richard H. Finnell1,5,4
1Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas
2The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
3Center for Molecular Development and Disease, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas
4Department of Pediatrics, University of Nebraska Medical Center, Omaha, Nebraska
5Center for Environmental and Rural Health, Texas A&M University, College Station, Texas

Tóm tắt

AbstractBACKGROUND: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. Birth Defects Research (Part A) 2007. © 2007 Wiley‐Liss, Inc.

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Wiley

Tập 79 Số 4

257-268

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