Developmental consequences of abnormal folate transport during murine heart morphogenesis

Tang, Louisa S.; Wlodarczyk, Bogdan J.; Santillano, Daniel R; Miranda, Rajesh C.; Finnell, Richard H.

doi:10.1002/bdra.20043

Cited by 66 publications

(61 citation statements)

References 47 publications

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“…We observed that the phenotypic defects induced after a single exposure to Li during gastrulation (Chen et al, 2008) are similar to those reported by others for elevated HCy in a transgenic mouse model (Tang et al, 2004). Because of the similarities in the cardiac and neural anomalies induced by either HCy or Li exposure, and because Li is known to mimic Wnt-β-catenin signaling, we hypothesized that both HCy and Li may target canonical Wnt signaling during the same early developmental window, but that this modulation of the pathway occurs at different regulatory levels.…”

Section: Introductionsupporting

confidence: 90%

“…Low dietary folate (folic acid, FA) and mutations in methylenetetrahydrofolate reductase (MTHFR) lead to elevated maternal plasma HCy levels. Elevated HCy increases the risk for neural tube, neural crest, craniofacial and congenital heart defects in the offspring (Boot et al, 2004;Huhta et al, 2006;Rosenquist et al, 1996;Tang et al, 2004). The association with elevated HCy is particularly strong for specific outflow tract defects, including pulmonary valve stenosis, coarctation of the aorta, and aortic valve stenosis (Huhta et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

Han

Serrano

Lastra-Vicente

et al. 2009

Disease Models &Amp; Mechanisms

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SUMMARY Elevated plasma homocysteine (HCy), which results from folate (folic acid, FA) deficiency, and the mood-stabilizing drug lithium (Li) are both linked to the induction of human congenital heart and neural tube defects. We demonstrated previously that acute administration of Li to pregnant mice on embryonic day (E)6.75 induced cardiac valve defects by potentiating Wnt–β-catenin signaling. We hypothesized that HCy may similarly induce cardiac defects during gastrulation by targeting the Wnt–β-catenin pathway. Because dietary FA supplementation protects from neural tube defects, we sought to determine whether FA also protects the embryonic heart from Li- or HCy-induced birth defects and whether the protection occurs by impacting Wnt signaling. Maternal elevation of HCy or Li on E6.75 induced defective heart and placental function on E15.5, as identified non-invasively using echocardiography. This functional analysis of HCy-exposed mouse hearts revealed defects in tricuspid and semilunar valves, together with altered myocardial thickness. A smaller embryo and placental size was observed in the treated groups. FA supplementation ameliorates the observed developmental errors in the Li- or HCy-exposed mouse embryos and normalized heart function. Molecular analysis of gene expression within the avian cardiogenic crescent determined that Li, HCy or Wnt3A suppress Wnt-modulated Hex (also known as Hhex) and Islet-1 (also known as Isl1) expression, and that FA protects from the gene misexpression that is induced by all three factors. Furthermore, myoinositol with FA synergistically enhances the protective effect. Although the specific molecular epigenetic control mechanisms remain to be defined, it appears that Li or HCy induction and FA protection of cardiac defects involve intimate control of the canonical Wnt pathway at a crucial time preceding, and during, early heart organogenesis.

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Section: Introductionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

Han

Serrano

Lastra-Vicente

et al. 2009

Disease Models &Amp; Mechanisms

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“…Thus, it may be suggested that FA treatment affects the expression of transcription factors and prevents the cardiac outflow tract defects. Furthermore, Tang et al reported that congenital heart defects in Folbp1 (-/-) mice were prevented by folic acid supplementation [39]. They demonstrated that this preventive effect is due to reduced apoptosis of cardiac neural crest cells that is associated with the expression of Pax-3 in cardiac neural crest cells.…”

Section: Discussionmentioning

confidence: 99%

Folic Acid Prevents Congenital Malformations in the Offspring of Diabetic Mice

et al. 2009

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Abstract. It is well known that maternal diabetes causes various congenital malformations. Although there are many reports that folic acid (FA) administration in pregnancy reduces the risk of birth defects including neural tube defects (NTDs), a precise analysis on the preventive effect of FA against diabetic embryopathy has not been done yet. In this study, we analyzed the preventive effects of FA on congenital malformations including NTDs, cardiovascular, and skeletal malformations using a diabetic mouse model. Female mice were rendered hyperglycemic by streptozotocin and then mated. Pregnant diabetic mice were treated daily with FA (3 mg/kg body weight) or saline between gestational days (GD) 6 and 10. On GD 18, fetuses were examined for congenital malformations. FA did not affect plasma glucose levels. In the DM control group, the incidence of NTDs, cardiovascular, and skeletal malformations was 28.4%, 28.5%, and 29.7%, respectively. In the FA-treated group, the corresponding proportions reduced to 6.0%, 2.5% and 12.5%, respectively. A whole-mount TUNEL revealed an increased apoptosis in the hindbrain region of embryos from DM control group on day 9.5, and the apoptosis was decreased by FA treatment. Maternal plasma homocysteine levels on GD 9.5 were significantly lowered in DM control group compared with those in non-DM group, and FA treatment did not show a significant effect. These results indicate that FA is effective for the prevention of various diabetic embryopathy including NTDs, cardiovascular, and skeletal malformations, and suggested that this effect is independent from homocysteine metabolism and possibly mediated by decreasing the abnormal apoptosis during organogenesis.

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“…In vitro studies found that an impaired folate and homocysteine metabolism affect the neural crest cells formation and migration [1,26]. Tang et al( 2004) [27] observed that reduced availability of folate by inactivating the folate transporter, Folbp1, in mice leads to an extensive reduction of migrating cardiac neural crest cells. The authors observed neural crest cell-associated CHD, including the improper septation, persistent truncus arteriosus, and doubleoutlet right ventricle.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants in the Methylenetetrahydrofolate Reductase Gene in Egyptian Children with Conotruncal Heart Defects and their Mothers

Kotby

Anwar

Elmasry

et al. 2012

Macedonian Journal of Medical Sciences

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Aim: This study aimed at evaluation of MTHFR 677C/T and 1298A/C polymorphisms in MTHFR gene as maternal risk factors in conotruncal heart defects (CTDs). Material and Methods:Thirty cases with CTDs and their mothers and thirty control children and their mothers were studied. Medical and nutritional histories for all mothers were taken with emphasis on folate intake. The mutations in MTHFR gene are a C to T substitution at base pair 677 and a A to C at base pair1298 were investigated by polymerase-chain reaction, followed by restriction enzyme digestion and detection by electrophoresis.Results: Folic acid intake was below the recommended daily allowance in case mothers compared to control mothers. No significant difference between patients and control group or their mothers regarding MTHFR gene polymorphisms at exon 4. Significant difference between case and control groups and between their mothers regarding MTHFR gene polymorphisms at exon 7. Homozygous genotype frequencies of MTHFR at position 1298 was significantly higher in cases and their mothers with an odds ratio 56 (95% confidence interval 10.3-303.7).Conclusion: Egyptian population may have high incidence of MTHFR polymorphism at exon 7 rather than at exon 4. Preconception folate intake might decrease MTHFR polymorphism at exon 7 and decrease risk of CTD.

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Developmental consequences of abnormal folate transport during murine heart morphogenesis

Abstract: Our findings demonstrate for the first time a prominent role of the Folbp1 gene in mediating susceptibility to heart defects.

Cited by 66 publications

References 47 publications

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

Folic Acid Prevents Congenital Malformations in the Offspring of Diabetic Mice

Genetic Variants in the Methylenetetrahydrofolate Reductase Gene in Egyptian Children with Conotruncal Heart Defects and their Mothers

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