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J. Cardiovasc. Dev. Dis. 2018, 5(4), 49; https://doi.org/10.3390/jcdd5040049

Defective Vagal Innervation in Murine Tbx1 Mutant Hearts

1
INSERM UMRS 1155, Centre for Kidney Research, 4 Rue de la Chine, 75020 Paris, France
2
UCL Great Ormond Street-Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
3
William Harvey Heart Centre, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
4
Department of Medicine, Rayne Institute, University College London, London WC1E 6JJ, UK
*
Author to whom correspondence should be addressed.
Received: 20 July 2018 / Revised: 17 September 2018 / Accepted: 20 September 2018 / Published: 23 September 2018
(This article belongs to the Special Issue Genetics of Congenital Heart Disease)
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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. View Full-Text
Keywords: Tbx1; DiGeorge Syndrome; neural crest cells; cranial nerves; innervation Tbx1; DiGeorge Syndrome; neural crest cells; cranial nerves; innervation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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MDPI and ACS Style

Calmont, A.; Anderson, N.; Suntharalingham, J.P.; Ang, R.; Tinker, A.; Scambler, P.J. Defective Vagal Innervation in Murine Tbx1 Mutant Hearts. J. Cardiovasc. Dev. Dis. 2018, 5, 49.

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