305 Conotruncal and coronary artery development in two mouse models of congenital heart defects

Abstract

Conotruncal heart defects are among the most frequent congenital heart diseases. Coronary artery anomalies are commonly associated with outflow tract malformations. The molecular and cellular mechanisms underlying their development have yet to be unravelled. TBX1, encoding a T-box transcription factor, is the major DiGeorge syndrome (del22q11.2) candidate gene and is required for pharyngeal and cardiovascular development. Tbx1-/- embryos have severe cardiac anomalies including a common arterial trunk. DiGeorge syndrome patients have a high incidence of conotruncal defects including persistant truncus arteriosus and tetralogy of Fallot. We have shown that the common arterial trunk in Tbx1-/- embryos has an aorta-like phenotype associated with severe reduction of a subpopulation of second heart field progenitor cells normally contributing to myocardium at the base of pulmonary trunk. Underdevelopment of subpulmonary myocardium is thought to be the primary defect in human conotruncal defects like tetralogy of Fallot. Anomalous coronary artery patterning occurs in Tbx1-/- hearts. Semaphorin3c, encoding a neurovascular guidance molecule is expressed in a Tbx1-dependent domain in the subpulmonary myocardium. Disruption of the semaphorin signaling pathway during heart morphogenesis results in outflow tract defects and anomalies of the aortic arch arteries. Sema3c-/- embryos also display common arterial trunk with interruption of the aortic arch but coronary artery patterning appears normal. Here we present a comparative analysis of the evolution of common trunk in these two models and investigate potential genetic interaction between these genes. Future subaortic and subpulmonary regions are prefigured in the E10.5 outflow tract. Using a candidate gene approach and microarray analysis at E10.5 we aim to identify additional genes expressed in subpulmonary myocardium that may contribute to conotruncal and coronary artery development.