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

Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A and M University System Health Science Center, Houston, Texas, USA. hzhu@ibt.tamhsc.edu

Birth defects research. Part A, Clinical and molecular teratology 2007 Apr

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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. We herein describe abnormal cardiovascular development in mouse fetuses lacking a functional fola te-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. 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 embr yonic 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. 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.

Citation

Huiping Zhu, Bogdan J Wlodarczyk, Melissa Scott, Wei Yu, Michelle Merriweather, Janee Gelineau-van Waes, Robert J Schwartz, Richard H Finnell. Cardiovascular abnormalities in Folr1 knockout mice and folate rescue. Birth defects research. Part A, Clinical and molecular teratology. 2007 Apr;79(4):257-68