Abstract
Haploinsufficiency of the T-box transcription factor TBX1 is responsible for many features of 22q11.2 deletion syndrome. Tbx1 is expressed dynamically in the pharyngeal apparatus during mouse development and Tbx1 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 Tbx1 mutant embryos. In this report, we used an allelic series of Tbx1 mouse mutants, embryo tissue explants and cardiac electrophysiology to characterise, in detail, the function of Tbx1 in vagal innervation of the heart. We found that total nerve branch length was significantly reduced in Tbx1+/− and Tbx1neo2/− mutant hearts expressing 50% and 15% levels of Tbx1. We also found that neural crest cells migrated normally to the heart of Tbx1+/−, but not in Tbx1neo2 mutant embryos. In addition, we showed that cranial ganglia IXth and Xth were fused in Tbx1neo2/− 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 Tbx1+/− animals versus controls. We speculate that this condition of decreased parasympathetic drive could result in a pro-arrhythmic substrate in some 22q11.2DS patients.
Highlights
22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans associated with a typical 3MB deletion within chromosome 22 [1,2]. 22q11.2DS patients exhibit craniofacial and ear anomalies, glandular defects, dysphagia and psychiatric illnesses [3]
We found that Tbx1 regulates epibranchial ganglion positioning, cNCC migratory paths and subsequent vagal nerve projections to the heart
We found that Tbx1 controls cardiac innervation in a non-cell autonomous fashion and that Tbx1+/− mutants show evidence of subtle abnormal vagal and muscarinic regulation of heart rate compared to their littermate controls
Summary
22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans associated with a typical 3MB deletion within chromosome 22 [1,2]. 22q11.2DS patients exhibit craniofacial and ear anomalies, glandular defects, dysphagia and psychiatric illnesses [3]. In addition to controlling the development of pharyngeal arch, glandular and cardiac derivatives typically affected in 22q11.2DS phenotypes, we and others have shown that shown that Tbx is involved in the regulation of cranial nerves and associated neural crest cell (NCC) migratory pathways [8,9]. The vagus nerve is the tenth of twelve paired cranial nerves It conveys mostly afferent fibres with sensory functions but has efferent components. The nodose placode contributes to the vagus sensory ganglion, which consists of both NCC- and epibranchial placode-derived neurons [13]. NCCs, which migrate to the dorsal aorta, differentiate into neurons and extend axonal projections into the cardiac tissue, and provide all of the efferent parasympathetic innervation to the heart [14]. We analyse the implication of this vagal nerve deficit for the innervation of a single defined peripheral compartment: the mouse heart
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
