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Embryonic Consequences of Abnormal Folate Transport: Impact on Congenital Heart Defects
Author(s) -
Finnell Richard H,
Wong Leeyean,
Zhu Huiping,
Cabrera Robert,
Maddox Joyce,
Rosenquist Thomas,
Waes Janee GelineauVan
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.lb40-a
Subject(s) - truncus arteriosus , neural tube , heart development , wnt signaling pathway , neural crest , biology , great arteries , teratology , double outlet right ventricle , oxidative stress , medicine , heart disease , embryonic stem cell , endocrinology , tetralogy of fallot , fetus , microbiology and biotechnology , embryo , gene , genetics , pregnancy , signal transduction
Recent human epidemiological studies have demonstrated that maternal periconceptional supplementation with folic acid is associated with a significant risk reduction for several complex birth defects, including spina bifida and other neural tube defects, cleft lip and palate, and conotruncal heart defects. To better understand the underlying mechanisms, we have used the folate receptor (Folbp1) knockout mouse as a model for studying the role of folate supplementation in the prevention of congenital heart defects. Folbp1 nullizygous embryos receiving insufficient folate to support normal development present with septation defects of the outflow tract, similar to those observed following cardiac neural crest cell (NCC) ablation. These phenotypic changes include: ventricular septal defects, double‐outlet right ventricle, persistent truncus arteriosus, anomalous aortic arch arteries, and abnormal looping of the heart. There are notable changes in these embryos at both the molecular and cellular levels. Results from DNA microarray studies revealed a significant alteration in the expression of key regulators of NCC migration, for genes related to reactive oxidative stress, and highlighted the importance of genes in the Wnt signaling and Shh pathways. At the cellular level, the data obtained from this mouse model suggest that many of the underlying defects can be traced back to increased apoptosis in cardiac NCC precursors of Folbp1 nullizygotes. High dose maternal folinic acid supplementation restores normal patterns of gene expression and rescues the normal cardiac phenotype. Supported in part by NIH grant HL66398 and The Texas Institute for Genomic Medicine