Neuregulin-1 promotes formation of the murine cardiac conduction system

Rentschler, Stacey; Zander, Jennifer; Meyers, Kathleen N.; Levine, Rebecca; Porter, George A.; Rivkees, Scott A.; Morley, Gregory E.; Fishman, Glenn I.

doi:10.1073/pnas.162301699

Cited by 222 publications

(216 citation statements)

References 32 publications

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“…CCS|lacZ, on the other hand, has been reported to have marker expression in the SAN region in early embryonic and neonatal time points (personal communication and [29]), but our study does not show any SAN expression in adult hearts. In some mice with this genotype, we found marker expression in the tissue around the SAN along the ICR, which in a whole mount would give an impression of β-gal expression in the SAN (supplemental Fig.…”

Section: Discussioncontrasting

confidence: 84%

“…These cells continue to retain their primitive phenotype and contribute to the formation of the CCS, septae and valves [31][32][33]. In the second model, vascular endothelium or endocardium is believed to emit paracrine signals that induce recruitment and re-differentiation of the periarteiolar working myocardium into the CCS, especially in the AVCS [29,[34][35][36]. Finally in a third scenario, it has been proposed that neural crest cells migrating from the posterior rhomboencephalons contribute or signal the generation of the CCS from the myocardium [37][38][39].…”

Section: Discussionmentioning

confidence: 99%

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Characterization of sinoatrial node in four conduction system marker mice

Viswanathan

Burch

Fishman

et al. 2007

Journal of Molecular and Cellular Cardiology

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The specialized cardiac conduction system (CCS) consists of the sinoatrial node (SAN) and the atrioventricular (AV) conduction system (AVCS), which includes proximal (AV node, bundle of His and bundle branches) and distal (Purkinje fibers) components. In four CCS marker mice [two transgenic (cGATA6|lacZ, CCS|lacZ) and two targeted gene knock-in (minK|lacZ, Hop|lacZ)] the expression of the lacZ gene (β-gal) has been reported to mark portions of the proximal and distal AVCS; the expression of this marker in the adult SAN is unknown. The primary objective of this study was to analyze the utility of these marker mice in the identification of the SAN. Intercaval and interventricular septal regions, containing all the components of the CCS, were freshly dissected from adult mice based on the anatomical landmarks and sectioned. Immunohistochemical characterization was performed with SAN markers (Cx45, HCN4), compared to the reporter expression (β-gal) and markers of the working myocardium (Cx40 and Cx43). In all four of the CCS marker mice, we found that β-gal expression is consistently observed in the proximal and distal AVCS. However, the presence of lacZ gene expression in the working myocardium outside the CCS and/or the absence of this reporter expression in the SAN prevent the effective use of these mice to identify the SAN, leading us to conclude that none of the four CCS marker mice we studied specifically mark the SAN.

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Section: Discussioncontrasting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Characterization of sinoatrial node in four conduction system marker mice

Viswanathan

Burch

Fishman

et al. 2007

Journal of Molecular and Cellular Cardiology

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“…At the cellular level, efficient impulse propagation through this network is dependent upon the interplay between cell morphology, membrane excitability, and electrical coupling of adjacent cells via gap junctions, the latter of which is the major determinant for rapid and directional conduction (3). Although regulation of early VCS specification and morphogenesis is becoming well understood (4)(5)(6)(7)(8)(9), less is known about how cells of the VCS gain their specialized conduction properties as they mature.…”

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confidence: 99%

Iroquois homeobox gene 3 establishes fast conduction in the cardiac His–Purkinje network

Zhang

Kim²,

Rosén³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

111

131

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Rapid electrical conduction in the His-Purkinje system tightly controls spatiotemporal activation of the ventricles. Although recent work has shed much light on the regulation of early specification and morphogenesis of the His-Purkinje system, less is known about how transcriptional regulation establishes impulse conduction properties of the constituent cells. Here we show that Iroquois homeobox gene 3 (Irx3) is critical for efficient conduction in this specialized tissue by antithetically regulating two gap junction-forming connexins (Cxs). Loss of Irx3 resulted in disruption of the rapid coordinated spread of ventricular excitation, reduced levels of Cx40, and ectopic Cx43 expression in the proximal bundle branches. Irx3 directly represses Cx43 transcription and indirectly activates Cx40 transcription. Our results reveal a critical role for Irx3 in the precise regulation of intercellular gap junction coupling and impulse propagation in the heart. development | electrophysiology | transcription factor

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“…Formation of the PVCS is stimulated by the endocardium-derived paracrine factors, neuregulin-1 (Rentschler et al 2002) and endothelin (Yanagisawa et al 1988, Masaki et al 1991, Gourdie et al 1998. The idea that the TR 1 isoform has a specific role in the PVCS because of its restricted expression is supported by data which show that the effect of endothelin is enhanced in rat cardiomyocyte cells transfected with TR 1, resulting in hypertrophy and expression of specific proteins (Liang et al 2003).…”

Section: Figurementioning

confidence: 99%

Expression pattern and ontogenesis of thyroid hormone receptor isoforms in the mouse heart

Stoykov¹,

Zandieh-Doulabi²,

Moorman³

et al. 2006

Journal of Endocrinology

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Nuclear thyroid hormone (T 3 ) receptors (TR) play a critical role in mediating the effects of T 3 on development, differentiation and normal physiology of many organs. The heart is a major target organ of T 3 , and recent studies in knockout mice demonstrated distinct effects of the different TR isoforms on cardiac function, but the specific actions of TR isoforms and their specific localization in the heart remain unclear. We therefore studied the expression of TR 1, TR 2 and TR 1 isoforms in the mouse heart at different stages of development, using monoclonal antibodies against TR 1, TR 2 and TR 1. In order to identify distinct components of the embryonic heart, in situ hybridization for cardiac-specific markers was used with the expression pattern of sarcoplasmic reticulum calcium-ATPase 2a as a marker of myocardial structures, while the pattern of expression of connexin40 was used to indicate the developing chamber myocardium and peripheral ventricular conduction system. Here we show that in the ventricles of the adult heart the TR 1 isoform is confined to the cells that form the peripheral ventricular conduction system. TR 1, on the other hand, is present in working myocardium as well as in the peripheral ventricular conduction system. In the atria and in the proximal conduction system (sinoatrial node, atrioventricular node), TR 1 and TR 1 isoforms are coexpressed. We also found the heterogeneous expression of the TR 1, TR 2 and TR 1 isoforms in the developing mouse heart, which, in the case of the TR 1 isoform, gradually revealed a dynamic expression pattern. It was present in all cardiomyocytes at the early stages of cardiogenesis, but from embryonic day 11·5 and into adulthood, TR 1 demonstrated a gradual confinement to the peripheral ventricular conduction system (PVCS), suggesting a specific role of this isoform in the formation of PVCS. Detailed knowledge of the distribution of TR 1 and TR 1 in the heart is of importance for understanding not only their mechanism of action in the heart but also the design and (clinical) use of TR isoform-specific agonists and antagonists.

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Neuregulin-1 promotes formation of the murine cardiac conduction system

Cited by 222 publications

References 32 publications

Characterization of sinoatrial node in four conduction system marker mice

Characterization of sinoatrial node in four conduction system marker mice

Iroquois homeobox gene 3 establishes fast conduction in the cardiac His–Purkinje network

Expression pattern and ontogenesis of thyroid hormone receptor isoforms in the mouse heart

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