Abstract
BackgroundHeart anomalies are the most frequently observed among all human congenital defects. As with the situation for neural tube defects (NTDs), it has been demonstrated that women who use multivitamins containing folic acid peri-conceptionally have a reduced risk for delivering offspring with conotruncal heart defects [1-3]. Cellular folate transport is mediated by a receptor or binding protein and by an anionic transporter protein system. Defective function of the Folr1 (also known as Folbp1; homologue of human FRα) gene in mice results in inadequate transport, accumulation, or metabolism of folate during cardiovascular morphogenesis.ResultsWe have observed cardiovascular abnormalities including outflow tract and aortic arch arterial defects in genetically compromised Folr1 knockout mice. In order to investigate the molecular mechanisms underlying the failure to complete development of outflow tract and aortic arch arteries in the Folr1 knockout mouse model, we examined tissue-specific gene expression difference between Folr1 nullizygous embryos and morphologically normal heterozygous embryos during early cardiac development (14-somite stage), heart tube looping (28-somite stage), and outflow track septation (38-somite stage). Microarray analysis was performed as a primary screening, followed by investigation using quantitative real-time PCR assays. Gene ontology analysis highlighted the following ontology groups: cell migration, cell motility and localization of cells, structural constituent of cytoskeleton, cell-cell adhesion, oxidoreductase, protein folding and mRNA processing. This study provided preliminary data and suggested potential candidate genes for further description and investigation.ConclusionThe results suggested that Folr1 gene ablation and abnormal folate homeostasis altered gene expression in developing heart and conotruncal tissues. These changes affected normal cytoskeleton structures, cell migration and motility as well as cellular redox status, which may contribute to cardiovascular abnormalities in mouse embryos lacking Folr1 gene activity.
Highlights
Heart anomalies are the most frequently observed among all human congenital defects
Conotruncal defects are a group of defects which result from abnormal aortico-pulmonary septation of the outflow tract of the heart, a process that has been shown to have a major mesectodermal cell contribution [6,7,8,9,10]
Embryos collected from s-folinic acid supplemented dams (Table 1) The average somite number of nullizygous embryos collected at E9.5 was 12.8 (± 3.3)
Summary
Heart anomalies are the most frequently observed among all human congenital defects. As with the situation for neural tube defects (NTDs), it has been demonstrated that women who use multivitamins containing folic acid peri-conceptionally have a reduced risk for delivering offspring with conotruncal heart defects [1,2,3]. Conotruncal defects are a group of defects which result from abnormal aortico-pulmonary septation of the outflow tract of the heart, a process that has been shown to have a major mesectodermal cell contribution [6,7,8,9,10]. Despite this understanding of the pathogenesis of conotruncal defects, little is known about the etiology of these heart defects. Most of the frontline anticonvulsants are known to be folate antagonists [14], and reduction in the bioavailability of folate to the fetus has been proposed as one of their potential underlying teratogenic mechanisms of action [15,16]
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