This Article Full Text Full Text (PDF) All Versions of this Article: 98/3/421    most recent 01.RES.0000202800.85341.6ev1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bajolle, F. Articles by Buckingham, M. E. Search for Related Content PubMed PubMed Citation Articles by Bajolle, F. Articles by Buckingham, M. E. Related Collections Cardiac development Genetics of cardiovascular disease Animal models of human disease Developmental biology Pediatric and congenital heart disease, including cardiovascular surgery Gene expression

(Circulation Research. 2006;98:421.)
© 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

Fanny Bajolle^*, Stéphane Zaffran^*, Robert G. Kelly, Juliette Hadchouel, Damien Bonnet, Nigel A. Brown, Margaret E. Buckingham

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 Pitx2c 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

This article has been cited by other articles:

				M. L. Kirby Pulmonary Atresia or Persistent Truncus Arteriosus: Is It Important to Make the Distinction and How Do We Do It? Circ. Res., August 15, 2008; 103(4): 337 - 339. [Full Text] [PDF]

				D Obler, A L Juraszek, L B Smoot, and M R Natowicz Double outlet right ventricle: aetiologies and associations J. Med. Genet., August 1, 2008; 45(8): 481 - 497. [Abstract] [Full Text] [PDF]

				M. Theveniau-Ruissy, M. Dandonneau, K. Mesbah, O. Ghez, M.-G. Mattei, L. Miquerol, and R. G. Kelly The del22q11.2 Candidate Gene Tbx1 Controls Regional Outflow Tract Identity and Coronary Artery Patterning Circ. Res., July 18, 2008; 103(2): 142 - 148. [Abstract] [Full Text] [PDF]

				M. L. Bakker, B. J. Boukens, M. T.M. Mommersteeg, J. F. Brons, V. Wakker, A. F.M. Moorman, and V. M. Christoffels Transcription Factor Tbx3 Is Required for the Specification of the Atrioventricular Conduction System Circ. Res., June 6, 2008; 102(11): 1340 - 1349. [Abstract] [Full Text] [PDF]

				L. Ryckebusch, Z. Wang, N. Bertrand, S.-C. Lin, X. Chi, R. Schwartz, S. Zaffran, and K. Niederreither Retinoic acid deficiency alters second heart field formation PNAS, February 26, 2008; 105(8): 2913 - 2918. [Abstract] [Full Text] [PDF]

				B. C. Lin, R. Sullivan, Y. Lee, S. Moran, E. Glover, and C. A. Bradfield Deletion of the Aryl Hydrocarbon Receptor-associated Protein 9 Leads to Cardiac Malformation and Embryonic Lethality J. Biol. Chem., December 7, 2007; 282(49): 35924 - 35932. [Abstract] [Full Text] [PDF]

				M. S. Rana, N. C.A. Horsten, S. Tesink-Taekema, W. H. Lamers, A. F.M. Moorman, and M. J.B. van den Hoff Trabeculated Right Ventricular Free Wall in the Chicken Heart Forms by Ventricularization of the Myocardium Initially Forming the Outflow Tract Circ. Res., April 13, 2007; 100(7): 1000 - 1007. [Abstract] [Full Text] [PDF]

				N. M.S. van den Akker, D. G.M. Molin, P. P.W.M. Peters, S. Maas, L. J. Wisse, R. van Brempt, C. J. van Munsteren, M. M. Bartelings, R. E. Poelmann, P. Carmeliet, et al. Tetralogy of Fallot and Alterations in Vascular Endothelial Growth Factor-A Signaling and Notch Signaling in Mouse Embryos Solely Expressing the VEGF120 Isoform Circ. Res., March 30, 2007; 100(6): 842 - 849. [Abstract] [Full Text] [PDF]