Regulation of the Epithelial–Mesenchymal Transformation through Gap Junction Channels in Heart Development

doi:10.1016/S1050-1738(01)00103-7

Trends in Cardiovascular Medicine

Volume 11, Issue 6, August 2001, Pages 213-218

https://doi.org/10.1016/S1050-1738(01)00103-7 Get rights and content

Abstract

Analyses of mice lacking the gap junction protein, connexin45 (Cx45), have provided new insights into the essential roles of gap junction channels in early embryogenesis. Of great surprise is the function of Cx45 in the endothelium, where it is essential for synchronized activation of the transcription factor Nfatc1. This laterally synchronized regulation model extends the generally accepted vertical model, in which interactions between the endocardium and the myocardium induce endocardial cushion formation through the epithelial–mesenchymal transformation.

Section snippets

Development of the Endocardium and the Myocardium

The endocardial cushion plays major roles in the formation of valves and septa. The endothelium lining the atrioventricular canal and the outflow tract gives rise to the cushion mesenchymal cells through the epithelial–mesenchymal transformation (Figure 4; Eisenberg and Markwald 1995). These cells migrate through the loose acellular matrix called the cardiac jelly. Later in cushion development, the epicardial cells also contribute to the endocardial cushion through another

Molecular Signals Controlling Endocardial–Myocardial Interactions

Three major regulation systems are involved in endocardial–myocardial development. The first is a signal network consisting of EGF-related growth factor neuregulins and their receptor tyrosine kinases ErbBs (Olayioye et al. 2000). As shown in Figure 4, neuregulin-1 is expressed specifically in the endothelium of the developing heart. By contrast, ErbBs are expressed in the myocardium, including the trabeculae (ErbB2 and ErbB4), and in the endocardial cushion cells (ErbB3; Gassmann et al. 1995,

Possible Downstream Factors of Cx45

Among the gap junction proteins, Cx45 is characterized by its low unitary conductance and strong voltage dependence, suitable for a low, sustained Ca²+ rise, which Nfatc1 activation requires (Dolmetsch et al. 1997). To examine whether Cx45-deficiency could affect Nfatc1 activity, the embryonic hearts were stained with an Nfatc1 antibody (Figure 3). In the control embryos, active nuclear Nfatc1 is found in almost all the endocardial endothelial cells. However, surprisingly, most of the entire

Other Roles of Cx45 during Development

Early lethality of the Cx45-deficient mice makes further analyses rather difficult. This may be one reason why two independent groups have reached different conclusions Krüger et al. 2000, Kumai et al. 2000. Because Cx45 is expressed in almost all the tissues of the gastrulation stage embryo, it is very likely that the Cx45 gap junction protein plays other roles in different tissues. Our expectation is that the laterally synchronized regulation model would hold true in the other developing

Summary

In early cardiogenesis, Cx45 is preferentially expressed to establish organized unidirectional blood flow. Physiologically, the Cx45 gap junctions are used to transmit coordinated excitation waves among the cardiac myocytes. Developmentally, Cx45 has essential roles in both producing the endocardial cushion and growth of myocardial trabeculae. The latter roles are ascribed to synchronized activation of the endothelium through sustained Ca²+ rises mediated by the Cx45 gap junction channels.

Acknowledgements

The authors thank Dr. Kei-ichiro Nakamura for critical reading of this manuscript. This work was supported by Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science (No. 11470005 and 12770007).

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This result strongly suggests that impaired fluid force and electrical control principally lead to aberrant cardiogenesis in the Cx45-deficient heart. Expression of Cx40 and Cx43 starts around E9.5, when the entire primitive ventricle begins to contract almost simultaneously, replacing former peristaltic contractions, likely due to the emerging conduction system [75,77]. Bundle branch dysfunctions in Cx40-deficient embryos appear around E14.5 and become more prominent in later stages [47,93,102].
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Brief reviewsRegulation of the Epithelial–Mesenchymal Transformation through Gap Junction Channels in Heart Development

Abstract

Section snippets

Development of the Endocardium and the Myocardium

Molecular Signals Controlling Endocardial–Myocardial Interactions

Possible Downstream Factors of Cx45

Other Roles of Cx45 during Development

Summary

Acknowledgements

Neuron

Cell

Trends Cardiovasc Med

Trends Cardiovasc Med

Downregulation of connexin 45 gene products during mouse heart development

Circ Res

Cloning and developmental expression of the chick type II and type III TGFβ receptors

Dev Dyn

Requirement of type III TGF-β receptor for endocardial cell transformation in the heart

Science

Genomic circuits and the integrative biology of cardiac diseases

Nature

Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum

Nature

Expression pattern of connexin gene products at the early developmental stages of the mouse cardiovascular system

Circ Res

RNA and protein localisations of TGFβ2 in the early mouse embryo suggest an involvement in cardiac development

Development

Differential activation of transcription factors induced by Ca2+ response amplitude and duration

Nature

Targeted mutations of transforming growth factor-β genes reveal important roles in mouse development and adult homeostasis

Eur J Biochem

Molecular regulation of atrioventricular valvuloseptal morphogenesis

Circ Res

ErbB3 is required for normal cerebellar and cardiac developmenta comparison with ErbB2- and heregulin-deficient mice

Development

Brief reviews
Regulation of the Epithelial–Mesenchymal Transformation through Gap Junction Channels in Heart Development

Differential activation of transcription factors induced by Ca²+ response amplitude and duration