Developmental consequences of abnormal folate transport during murine heart morphogenesis.
BACKGROUND
Folic acid is essential for the synthesis of nucleotides and methyl transfer reactions. Folic acid-binding protein one (Folbp1) is the primary mediator of folic acid transport into murine cells. Folbp1 knockout mouse embryos die in utero with multiple malformations, including severe congenital heart defects (CHDs). Although maternal folate supplementation is believed to prevent human conotruncal heart defects, its precise role during cardiac morphogenesis remains unclear. In this study, we examined the role of folic acid on the phenotypic expression of heart defects in Folbp1 mice, mindful of the importance of neural crest cells to the formation of the conotruncus.


METHODS
To determine if the Folbp1 gene participates in the commitment and differentiation of the cardiomyocytes, relative levels of dead and proliferating precursor cells in the heart were examined by flow cytometry, Western blot, and immunohistostaining.


RESULTS
Our studies revealed that impaired folic acid transport results in extensive apoptosis-mediated cell death, which concentrated in the interventricular septum and truncus arteriosus, thus being anatomically restricted to the two regions of congenital heart defects. Together with a reduced proliferative capacity of the cardiomyocytes, the limited size of the available precursor cell pool may contribute to the observed cardiac defects. Notably, there is a substantial reduction in Pax-3 expression in the region of the presumptive migrating cardiac neural crest, suggesting that this cell population may be the most severely affected by the massive cell death.


CONCLUSIONS
Our findings demonstrate for the first time a prominent role of the Folbp1 gene in mediating susceptibility to heart defects.
Tang
Louisa S
LS
Center for Environmental and Genetic Medicine, Institute of Biosciences & Technology, Texas A&M University Health Science Center, Houston, Texas, USA.
Wlodarczyk
Bogdan J
BJ
Santillano
Daniel R
DR
Miranda
Rajesh C
RC
Finnell
Richard H
RH
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism*; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D058973:Folate Receptors, GPI-Anchored; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C068686:Pax3 protein, mouse; D005492:Folic Acid; D019098:Telomerase