The del22q11.2 Candidate Gene Tbx1 Controls Regional Outflow Tract Identity and Coronary Artery Patterning

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 phary...

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Bibliographic Details
Published in:Circulation research 2008-07, Vol.103 (2), p.142-148
Main Authors: Théveniau-Ruissy, Magali, Dandonneau, Mathieu, Mesbah, Karim, Ghez, Olivier, Mattei, Marie-Geneviève, Miquerol, Lucile, Kelly, Robert G
Format: Article
Language:English
Subjects:
Animals
Coronary Vessel Anomalies - genetics
Coronary Vessels - embryology
Coronary Vessels - physiopathology
DiGeorge Syndrome - genetics
DiGeorge Syndrome - physiopathology
Disease Models, Animal
Gene Expression Regulation, Developmental - physiology
Heart - embryology
Mice
Mice, Knockout
Mice, Transgenic
Pulmonary Artery - embryology
Pulmonary Artery - physiopathology
Regional Blood Flow - physiology
Semaphorins - genetics
T-Box Domain Proteins - genetics
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Summary: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 that contribute to the arterial pole of the heart. The outflow tract of Tbx1 mutant embryos is short and narrow resulting in common arterial trunk. Here we show by a series of genetic crosses using transgene markers of second heart field derived myocardium and coronary endothelial cells that a subdomain of myocardium normally observed at the base of the pulmonary trunk is reduced and malpositioned in Tbx1 mutant hearts. 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, proximal coronary arteries coursing 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 implicate second heart field development in coronary artery patterning and provide new insights into the association between conotruncal defects and coronary artery anomalies.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.108.172189