Résumé :
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TBX1, encoding a T-box containing transcription factor, is the major candidate gene for del22q11.2 or DiGeorge syndrome, characterized by craniofacial and cardiovascular defects including tetralogy of Fallot and common arterial trunk. Mice lacking Tbx1 have severe defects in the development of pharyngeal derivatives including cardiac progenitor cells of the second heart field contributing to the arterial pole of the heart. The outflow tract of mutant embryos is short and narrow and fails to septate resulting in a common arterial trunk. A series of crosses using transgene markers of the second heart field and coronary artery endothelial cells reveal that Tbx1 mutant hearts form in the absence or severe reduction of a specific subpopulation of progenitor cells normally giving rise to subpulmonary myocardium. The Tbx1 mutant ventricular outlet thus has an aorta-like morphology with three valve leaflets. This defect is associated with anomalous coronary artery patterning. Both right and left coronary ostia form predominantly at the right/ventral sinus in mutant hearts; as a result, proximal coronary arteries course across the normally coronary free ventral region of the heart. We have identified Semaphorin3c as a Tbx1-dependent gene expressed in subpulmonary myocardium. Our results provide new insights into the association between conotruncal defects and coronary artery anomalies and implicate second heart field derived cells in coronary artery patterning.
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