Impaired development of left anterior heart field by ectopic retinoic acid causes transposition of the great arteries.
BACKGROUND
Transposition of the great arteries is one of the most commonly diagnosed conotruncal heart defects at birth, but its etiology is largely unknown. The anterior heart field (AHF) that resides in the anterior pharyngeal arches contributes to conotruncal development, during which heart progenitors that originated from the left and right AHF migrate to form distinct conotruncal regions. The aim of this study is to identify abnormal AHF development that causes the morphology of transposition of the great arteries.


RESULTS
We placed a retinoic acid-soaked bead on the left or the right or on both sides of the AHF of stage 12 to 14 chick embryos and examined the conotruncal heart defect at stage 34. Transposition of the great arteries was diagnosed at high incidence in embryos for which a retinoic acid-soaked bead had been placed in the left AHF at stage 12. Fluorescent dye tracing showed that AHF exposed to retinoic acid failed to contribute to conotruncus development. FGF8 and Isl1 expression were downregulated in retinoic acid-exposed AHF, and differentiation and expansion of cardiomyocytes were suppressed in cultured AHF in medium supplemented with retinoic acid.


CONCLUSIONS
The left AHF at the early looped heart stage, corresponding to Carnegie stages 10 to 11 (28 to 29 days after fertilization) in human embryos, is the region of the impediment that causes the morphology of transposition of the great arteries.
Department of Anatomy and Cell Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan (M.N., T.K., T.Y., Y.N.).
Mayu
M
Narematsu
Department of Anatomy and Cell Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan (M.N., T.K., T.Y., Y.N.).
Tatsuya
T
Kamimura
Department of Anatomy and Cell Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan (M.N., T.K., T.Y., Y.N.).
Toshiyuki
T
Yamagishi
Laboratory of Statics, Graduate School of Medicine, Osaka City University, Osaka, Japan (M.F.).
Mitsuru
M
Fukui
Department of Anatomy and Cell Biology, Graduate School of Medicine, Osaka City University, Osaka, Japan (M.N., T.K., T.Y., Y.N.).
Yuji
Y
Nakajima
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002642:Chick Embryo; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000196:embryology*; D060850:LIM-Homeodomain Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D014157:Transcription Factors / Q000378:metabolism; D014188:Transposition of Great Vessels / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D014212:Tretinoin / Q000633:toxicity*
D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; D014212:Tretinoin; D005346:Fibroblast Growth Factors
Isl1; congenital; heart defects; morphogenesis; transposition of great vessel