In humans, TBX1 is the major candidate gene for DiGeorge (del22q11.2) syndrome, which includes heart malformations such as tetralogy of Fallot and Persistent Truncus Arteriosus (PTA). In Tbx1 null embryos, Second Heart Field (SHF) cardiac progenitor cell numbers are decreased leading to a hypoplastic outflow tract and PTA. Recently, we have shown that the Tbx1 phenotype is associated with reduction of a specific progenitor cell population that normally contributes to myocardium at the base of the pulmonary trunk. The Tbx1 mutant ventricular outlet thus has a predominantly subaortic identity supported by the presence of a single outflow valve with three leaflets. In addition, we demonstrated that coronary artery patterning is abnormal in Tbx1-nulls. Proximal coronary arteries course abnormally across the ventral region of mutant hearts and left and right arteries branch to the right/ventral sinus of the common outlet.

Coronary artery patterning defects are observed at early developmental stages at the level of the coronary plexus suggesting that SHF derived cells influence the cellular and molecular events responsible for the distribution and branching of proximal coronary arteries. We have identified Semaphorin3c as a Tbx1-dependent gene expressed in subpulmonary myocardium. However, Sema3c-null embryos do not show major coronary artery defects suggesting that Sema3c function overlaps with that of other genes affected in Tbx1 mutant embryos. We are now investigating the distribution and patterning of additional vascular guidance molecules as well as the distribution of neural crest cells and cardiac cushions which play critical roles in outflow tract development in wild type mice.

Our results provide new insights into the association between conotruncal defects and coronary artery anomalies and implicate SHF derived cells in coronary artery patterning. Ongoing research in collaboration with Necker Hospital (Paris) aims to investigate whether specific coronary artery anomalies are associated with PTA in DiGeorge syndrome.