Published online before print January 5, 2006, doi: 10.1161/01.RES.0000202800.85341.6e
© 2006 American Heart Association, Inc.
Integrative Physiology |
Rotation of the Myocardial Wall of the Outflow Tract Is Implicated in the Normal Positioning of the Great Arteries
From the Department of Developmental Biology (F.B., S.Z., M.B.), CNRS URA 2578, Pasteur Institute, Paris, France; Developmental Biology Institute of Marseille-Luminy (R.G.K.), CNRS UMR6216, Marseille, France; INSERM U.36 (J.H.), College de France, Paris; Service de Cardiologie Pédiatrique (D.B.), Hôpital Necker-Enfants-Malades AP-HP, Paris, France; and Division of Basic Medical Sciences (N.A.B.), St. George’s, University of London, United Kingdom.
Correspondence to Margaret Buckingham, Department of Developmental Biology, Pasteur Institute, 25 rue du Dr. Roux, 75015 Paris, France. E-mail margab{at}pasteur.fr
Congenital heart defects frequently involve a failure of outflow tract (OFT) formation during development. We analyzed the remodeling of the OFT, using the y96-Myf5-nlacZ-16 transgene, which marks a subpopulation of myocardial cells of the pulmonary trunk. Expression analyses of reporter transcript and protein suggest that the myocardial wall of the OFT rotates before and during the formation of the great arteries. Rotational movement was confirmed by Di-I injection experiments with cultured embryos. We subsequently examined the expression of the transgene in mouse models for OFT defects. In hearts with persistent truncus arteriosus (PTA), double outlet right ventricle (DORV), or transposition of the great arteries, rotation of the myocardial wall of the OFT is arrested or fails to initiate. This is observed in Splotch (Pax3) mutants with PTA or DORV and may be a result of defects in neural crest migration, known to affect OFT septation. However, in Pitx2
c mutant embryos, where cardiac neural crest cells are present in the heart, PTA and DORV are again associated with a rotation defect. This is also seen in Pitx2c mutants, which have transposition of the great arteries. Because Pitx2c is involved in left–right signaling, these results suggest that embryonic laterality affects rotation of the myocardial wall during OFT maturation. We propose that failure of normal rotation of OFT myocardium may underlie major forms of congenital heart disease.
Key Words: heart • outflow tract • Splotch • Pitx2 • transposition of the great arteries
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