Acetylcholinesterase in prenatal rat heart: A marker for the early development of the cardiac conductive tissue?

Lamers, Wouter H.; Korstschot, Anita Te; Los, J. M.; Moorman, Antoon F.M.

doi:10.1002/ar.1092170407

Cited by 60 publications

(26 citation statements)

References 32 publications

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“…Embryos and fetuses were obtained from timed pregnant rats as described before.14 Hearts from rats at 13,14,16, and 20 embryonic days (EDs), from neonates (ED 22), and from adult rats were studied. Because the monoclonal antibody against connexin32 was raised in rats, it was decided to study the expression pattern of this protein in mice.…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

“…Nicholson (SUNY, Buffalo, N.Y.) kindly provided us with two additional rabbit antibodies. The first antibody was raised against amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] of the amino terminal domain of connexin43, and the second antibody was raised against amino acids 302-319 at the carboxyl terminal domain of connexin43. The latter antibody was affinity-purified.…”

Section: Antibodiesmentioning

confidence: 99%

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Spatial distribution of connexin43, the major cardiac gap junction protein, in the developing and adult rat heart.

Kempen

Fromaget

Gros

et al. 1991

Circulation Research

175

100

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The developmental appearance and spatial distribution pattern of gap junctions were studied in prenatal and adult rat hearts. Gap junctions were visualized immunohistochemically with an antibody raised against a unique cytoplasmic epitope of connexin43, and the spatial distribution pattern was determined by three-dimensional reconstruction. The results demonstrate that from embryonic day 13 onward, connexin43 becomes detectable immunohistochemically in the myocardium of atria and ventricles. No expression is initially detectable in the myocardium of the sinus venosus, the sinoatrial node, the posterior wall of the atrium and pulmonary veins, the interatrial septum, the atrioventricular canal, including atrioventricular node and bundle, the interventricular septum, and the outflow tract. The developmental increase in the density of gap junctions in atria and ventricles of prenatal hearts correlates well with the reported developmental increase in conduction velocity. Whereas connexin43 becomes expressed in the derivatives of the sinus venosus (except for the sinoatrial node) and in the subepicardial layer of the ventricular free wall shortly before birth, it remains undetectable in the atrioventricular node and bundle and the proximal part of the ventricular conduction tissue, even in the adult heart. The apparent absence of an abundant expression of connexin43 at a location with a supposedly high conduction velocity (i.e., the atrioventricular bundle and bundle branches) is unexpected. These observations were confirmed in studies of the adult mouse heart, which showed, in addition, that connexin32 is not expressed in any part of the heart. (Circulation Research 1991;68:1638-1651 In the "primary myocardium" of early, tubular hearts the conduction of the depolarizing impulse, which initiates contraction of the myocytes, is slow and spreads uniformly, resulting in a peristaltic contraction pattern. Although the conduction velocity in the working myocardium of atria and ventricles increases during development, it remains low in the adjacent regions (sinus venosus, atrioventricular canal, and outflow tract, i.e., the remaining primary myocardium). As a result, the cardiac tube consists of a series of segments with alternatingly slow and relatively fast conduction velocities. These developmental changes in regional conduction velocity and contraction pattern are best documented for avian embryosl-5 but are believed to occur also in the embryonic mammalian heart.6 Since cardiac gap junctions are generally believed to be responsible for the direct electrical coupling between myocardial cells (for recent reviews see References 7-9), we hypothesized that the selective formation of gap junctions in working myocardium might explain the gradual appearance of a more rapid conduction of the depolarizing impulse in the developing atria and ventricles. As a first step to test this hypothesis, we have studied the spatial distribution of gap junctions in the developing rat heart. A gap junction consists of an array of cell-to-cell...

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Section: Materials and Methods Animalsmentioning

confidence: 99%

Section: Antibodiesmentioning

confidence: 99%

Spatial distribution of connexin43, the major cardiac gap junction protein, in the developing and adult rat heart.

Kempen

Fromaget

Gros

et al. 1991

Circulation Research

175

100

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“…We found that expression of Cx40 and Na v 1.5 was drastically reduced in the VCS after removal of Tbx5 ( Figure 5). The proximal AV bundle and distal AV bundle/bundle branches were identified by their anatomic location, acetylcholinesterase activity (12,(17)(18)(19), and contactin-2 expression (20). Tbx5 fl/fl controls demonstrated high Cx40 and Na v 1.5 expression throughout the molecularly defined VCS, whereas Tbx5 minKCreERT2 animals demonstrated dramatic Values are mean ± SD.…”

Section: Figurementioning

confidence: 99%

TBX5 drives Scn5a expression to regulate cardiac conduction system function

et al. 2012

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Cardiac conduction system (CCS) disease, which results in disrupted conduction and impaired cardiac rhythm, is common with significant morbidity and mortality. Current treatment options are limited, and rational efforts to develop cell-based and regenerative therapies require knowledge of the molecular networks that establish and maintain CCS function. Recent genome-wide association studies (GWAS) have identified numerous loci associated with adult human CCS function, including TBX5 and SCN5A. We hypothesized that TBX5, a critical developmental transcription factor, regulates transcriptional networks required for mature CCS function. We found that deletion of Tbx5 from the mature murine ventricular conduction system (VCS), including the AV bundle and bundle branches, resulted in severe VCS functional consequences, including loss of fast conduction, arrhythmias, and sudden death. Ventricular contractile function and the VCS fate map remained unchanged in VCS-specific Tbx5 knockouts. However, key mediators of fast conduction, including Na v 1.5, which is encoded by Scn5a, and connexin 40 (Cx40), demonstrated Tbx5-dependent expression in the VCS. We identified a TBX5-responsive enhancer downstream of Scn5a sufficient to drive VCS expression in vivo, dependent on canonical T-box binding sites. Our results establish a direct molecular link between Tbx5 and Scn5a and elucidate a hierarchy between human GWAS loci that affects function of the mature VCS, establishing a paradigm for understanding the molecular pathology of CCS disease. IntroductionThe cardiac conduction system (CCS) consists of a network of specialized cardiomyocytes that generate and propagate the electrical impulses that organize cardiac contraction. The CCS is composed of the slowly propagating atrial nodes, including the sinoatrial (SA) and atrioventricular (AV) nodes, and the rapidly propagating ventricular conduction system (VCS), including the AV (His) bundle and right and left bundle branches. The VCS is uniquely adapted for fast conduction in order to rapidly transmit the electrical impulse governing ventricular contraction from the AV node to the ventricular apex. Disorders of the VCS are common, carry significant morbidity, and are poorly understood from a molecular perspective.The transcriptional networks required to maintain function of the adult CCS are undefined. Our current understanding of the molecular mediators of CCS function stems largely from heritable monogenic disorders and mouse models that have identified a limited number of genes essential for maintaining cardiac rhythm, most of which encode ion channels and their interacting partners (reviewed in ref. 1). Similar approaches have also begun to uncover the transcriptional networks required for CCS development (reviewed in ref.2). Recent genome-wide association studies (GWAS) have identified loci implicated in ECG interval variation (3-8), providing candidate genes with potentially important roles in CCS function in the general population. Specifically, numerous loci near genes e...

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“…No CX40 has been detected in the sinoatrial or atrioventricular nodes, which are known to be CX40 deficient (Gros et al, 1994). Different markers that codistribute with the adult conduction system during its differentiation have been described: IC8 (Gorza and Vitadello, 19891, Leu-7 or HNKl (Ikeda et al, 1990;Nakagawa et al, 19931, aMHC/PMHC (De Groot et al, 1989), and AChE (Lamers et al, 1987). In contrast to these markers, CX40 is still expressed in adult heart and is known as a constitutive protein of the junctional channels directly involved in the conduction of the electrical impulse in the VCS.…”

Section: Distribution Of Cx40 In the Conduction Systemmentioning

confidence: 99%

Developmental regulation of connexin 40 gene expression in mouse heart correlates with the differentiation of the conduction system

Delorme

Dahl

Jarry-Guichard

et al. 1995

Developmental Dynamics

154

108

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In adult mouse heart, CX40 is expressed in the atria and the proximal part of the ventricular conduction system (the His bundle and the upper parts of the bundle branches). This cardiac tissue is specialized in the conduction of the electrical impulse. CX40 is the only mouse connexin known to be expressed in these parts of the adult conductive tissue and is thus considered as a marker of the conduction system. In the present report, we investigated CX40 expression and distribution during mouse heart development. We first demonstrate that CX40 mRNA is regulated throughout development, as are other heart connexin transcripts, i.e., CX37, CX43, and (2x45, with a decreasing abundance as development proceeds. We also show that the CX40 transcript and protein are similarly regulated, CX40 being expressed as two different phosphorylated and un-phosphorylated forms of 41 and 40 kDa, respectively. Surprisingly, distribution studies demonstrated that CX40 is widely expressed in 11 days post-coitum (dpc) embryonic heart, where it is detected in both the atria and ventricle primordia. As development proceeds, the CX40 distribution pattern in the atria is maintained, whereas a more dynamic pattern is observed in the ventricles. From 14 dpc onwards, as the adult ventricular conduction system differentiates, CX40 decreases in the trabecular network and it is preferentially distributed in the ventricular conduction system. CX40 is thus the marker of the early differentiating conduction system. It is hypothesized that the conduction system is present in unorganized "embryonic" form at 11 dpc and trans-differentiates by 14 dpc into the adult conduction system. 0 1995 Wiley-Liss, Inc.

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Acetylcholinesterase in prenatal rat heart: A marker for the early development of the cardiac conductive tissue?

Cited by 60 publications

References 32 publications

Spatial distribution of connexin43, the major cardiac gap junction protein, in the developing and adult rat heart.

Spatial distribution of connexin43, the major cardiac gap junction protein, in the developing and adult rat heart.

TBX5 drives Scn5a expression to regulate cardiac conduction system function

Developmental regulation of connexin 40 gene expression in mouse heart correlates with the differentiation of the conduction system

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