Tbx1 plays a critical role in focal adhesion dynamics through paxillin regulation.

The T-box transcription factor TBX1 is expressed in the cardio-pharyngeal mesoderm. The correct cell fate decisions of cardio-pharyngeal mesoderm cells are critical, as any defect in this process can alter second heart field morphogenesis and lead to cardiac outflow tract and pharyngeal apparatus defects. The second heart field plays a crucial role in cardiac development by incorporating cardiac progenitors into the heart. It is also the major gene implicated in 22q11.2 deletion (or DiGeorge) syndrome, a primary genetic cause of congenital heart defects associated with hypoplasia of the cardiac outflow tract. The murine model recapitulates the heart phenotype and shows anomalies in the ECM-integrin-focal adhesion pathway. Here, we used a cell culture model to manipulate Tbx1 levels in order to molecularly and functionally characterize the defective focal adhesions (FAs) caused by Tbx1 loss and to analyse their dynamics on the ECM. Intriguingly, we found that Tbx1 regulates FA dynamics by influencing the FA disassembly process. Furthermore, Tbx1 is required for the paxillin (PXN) signalling pathway and controls cell spreading primarily through Pxn regulation. In fact, consistent with this observation, the ectopic expression of PXN rescued the cell spreading and signalling defects caused by Tbx1 depletion. Finally, our study revealed that, at least in vitro, TBX1 is a critical regulator of cell adhesion by affecting FA turnover.