Defective Vagal Innervation in Murine Mutant Hearts.

Haploinsufficiency of the T-box transcription factor is responsible for many features of 22q11.2 deletion syndrome. is expressed dynamically in the pharyngeal apparatus during mouse development and homozygous mutants display numerous severe defects including abnormal cranial ganglion formation and neural crest cell defects. These abnormalities prompted us to investigate whether parasympathetic (vagal) innervation of the heart was affected in mutant embryos. In this report, we used an allelic series of mouse mutants, embryo tissue explants and cardiac electrophysiology to characterise, in detail, the function of in vagal innervation of the heart. We found that total nerve branch length was significantly reduced in and mutant hearts expressing 50% and 15% levels of . We also found that neural crest cells migrated normally to the heart of , but not in mutant embryos. In addition, we showed that cranial ganglia IX and X were fused in but neuronal differentiation appeared intact. Finally, we used telemetry to monitor heart response to carbachol, a cholinergic receptor agonist, and found that heart rate recovered more quickly in animals versus controls. We speculate that this condition of decreased parasympathetic drive could result in a pro-arrhythmic substrate in some 22q11.2DS patients.