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JCI Insight
2019 Oct 17;420:. doi: 10.1172/jci.insight.121971.
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Muscarinic receptors promote pacemaker fate at the expense of secondary conduction system tissue in zebrafish.
Burczyk MS
,
Burkhalter MD
,
Tena TC
,
Grisanti LA
,
Kauk M
,
Matysik S
,
Donow C
,
Kustermann M
,
Rothe M
,
Cui Y
,
Raad F
,
Laue S
,
Moretti A
,
Zimmermann WH
,
Wess J
,
Kühl M
,
Hoffmann C
,
Tilley DG
,
Philipp M
.
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Deterioration or inborn malformations of the cardiac conduction system (CCS) interfere with proper impulse propagation in the heart and may lead to sudden cardiac death or heart failure. Patients afflicted with arrhythmia depend on antiarrhythmic medication or invasive therapy, such as pacemaker implantation. An ideal way to treat these patients would be CCStissue restoration. This, however, requires precise knowledge regarding the molecular mechanisms underlying CCS development. Here, we aimed to identify regulators of CCS development. We performed a compound screen in zebrafish embryos and identified tolterodine, a muscarinic receptor antagonist, as a modifier of CCS development. Tolterodine provoked a lower heart rate, pericardiac edema, and arrhythmia. Blockade of muscarinic M3, but not M2, receptors induced transcriptional changes leading to amplification of sinoatrial cells and loss of atrioventricular identity. Transcriptome data from an engineered human heartmuscle model provided additional evidence for the contribution of muscarinic M3 receptors during cardiac progenitor specification and differentiation. Taken together, we found that muscarinic M3 receptors control the CCS already before the heart becomes innervated. Our data indicate that muscarinic receptors maintain a delicate balance between the developing sinoatrial node and the atrioventricular canal, which is probably required to prevent the development of arrhythmia.
Austin,
Molecular mechanisms of arrhythmogenic cardiomyopathy.
2019, Pubmed
Austin,
Molecular mechanisms of arrhythmogenic cardiomyopathy.
2019,
Pubmed
Benes,
Decrease in heart adrenoceptor gene expression and receptor number as compensatory tool for preserved heart function and biological rhythm in M(2) KO animals.
2012,
Pubmed
Brand,
Tbx18 and the generation of a biological pacemaker. Are we there yet?
2016,
Pubmed
Bressan,
Early mesodermal cues assign avian cardiac pacemaker fate potential in a tertiary heart field.
2013,
Pubmed
Burkhalter,
Grk5l controls heart development by limiting mTOR signaling during symmetry breaking.
2013,
Pubmed
Burns,
Purification of hearts from zebrafish embryos.
2006,
Pubmed
Burridge,
Chemically defined generation of human cardiomyocytes.
2014,
Pubmed
Chapple,
Muscarinic receptor antagonists in the treatment of overactive bladder.
2000,
Pubmed
Christoffels,
Formation of the venous pole of the heart from an Nkx2-5-negative precursor population requires Tbx18.
2006,
Pubmed
Christoffels,
Development of the pacemaker tissues of the heart.
2010,
Pubmed
Dietrich,
Blood flow and Bmp signaling control endocardial chamber morphogenesis.
2014,
Pubmed
Donahue,
Focal modification of electrical conduction in the heart by viral gene transfer.
2000,
Pubmed
Fisher,
Loss of vagally mediated bradycardia and bronchoconstriction in mice lacking M2 or M3 muscarinic acetylcholine receptors.
2004,
Pubmed
Fregoso,
Development of cardiac parasympathetic neurons, glial cells, and regional cholinergic innervation of the mouse heart.
2012,
Pubmed
Gomeza,
Pronounced pharmacologic deficits in M2 muscarinic acetylcholine receptor knockout mice.
1999,
Pubmed
Greulich,
Misexpression of Tbx18 in cardiac chambers of fetal mice interferes with chamber-specific developmental programs but does not induce a pacemaker-like gene signature.
2016,
Pubmed
Griffin,
Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome.
2017,
Pubmed
Hildreth,
Cells migrating from the neural crest contribute to the innervation of the venous pole of the heart.
2008,
Pubmed
Hoffmann,
Islet1 is a direct transcriptional target of the homeodomain transcription factor Shox2 and rescues the Shox2-mediated bradycardia.
2013,
Pubmed
Hsieh,
Zebrafish M2 muscarinic acetylcholine receptor: cloning, pharmacological characterization, expression patterns and roles in embryonic bradycardia.
2002,
Pubmed
Hu,
Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block.
2014,
Pubmed
Huang,
Germ-line transmission of a myocardium-specific GFP transgene reveals critical regulatory elements in the cardiac myosin light chain 2 promoter of zebrafish.
2003,
Pubmed
Husse,
Generation of cardiac pacemaker cells by programming and differentiation.
2016,
Pubmed
John,
Sinus Node and Atrial Arrhythmias.
2016,
Pubmed
Kapoor,
Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18.
2013,
Pubmed
Kelder,
The sinus venosus myocardium contributes to the atrioventricular canal: potential role during atrioventricular node development?
2015,
Pubmed
Keßler,
Recent progress in the use of zebrafish for novel cardiac drug discovery.
2015,
Pubmed
Mably,
heart of glass regulates the concentric growth of the heart in zebrafish.
2003,
Pubmed
Machleidt,
NanoBRET--A Novel BRET Platform for the Analysis of Protein-Protein Interactions.
2015,
Pubmed
Moens,
Whole mount RNA in situ hybridization on zebrafish embryos: hybridization.
2008,
Pubmed
Pandur,
Islet1-expressing cardiac progenitor cells: a comparison across species.
2013,
Pubmed
,
Xenbase
Peal,
Patterning and development of the atrioventricular canal in zebrafish.
2011,
Pubmed
Poon,
Development of the cardiac conduction system in zebrafish.
2016,
Pubmed
Stainier,
Zebrafish genetics and vertebrate heart formation.
2001,
Pubmed
Thisse,
High-resolution in situ hybridization to whole-mount zebrafish embryos.
2008,
Pubmed
Wallis,
Pre-clinical and clinical pharmacology of selective muscarinic M3 receptor antagonists.
1995,
Pubmed
Wang,
First quantitative high-throughput screen in zebrafish identifies novel pathways for increasing pancreatic β-cell mass.
2015,
Pubmed
Wang,
Functional M3 muscarinic acetylcholine receptors in mammalian hearts.
2004,
Pubmed
Yamada,
Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean.
2001,
Pubmed
Zeidler,
Computational Detection of Stage-Specific Transcription Factor Clusters during Heart Development.
2016,
Pubmed
de Pater,
Distinct phases of cardiomyocyte differentiation regulate growth of the zebrafish heart.
2009,
Pubmed
