Abstract
Heart muscle cells are electrically coupled by gap junctions, clusters of low-resistance transmembrane channels composed of connexins (Cx). The expression of the three major connexins (Cx43, Cx40 and Cx45) present in cardiac myocytes is known to be developmentally regulated but it is not clear how the patterns in the human heart compare with those found in the mouse. This issue is of importance given the wide use of transgenic mice to investigate gene function with the aim of extrapolating the results to human. In the present study we applied immunoconfocal microscopy to investigate the spatial distribution of the three connexins in the developing mouse heart and foetal human heart. Although Cx45 labelling was present at low levels throughout the developing mouse heart and human foetal (9-week) heart, it was most prominent in the conduction tissues. In the developing mouse heart, Cx40 was widely expressed at embryonic day 12.5 (E12.5) but at E17.5 expression was restricted to the conduction tissues and atria. In the 9-week human foetal heart, the Cx40 labelling pattern was similar to the E15 mouse heart, being far more abundant in conduction tissues (bundle branches to Purkinje fibres) and atria than in the ventricular muscle. Cx43 labelling became more apparent in the ventricular myocardium as development of the mouse heart progressed but was virtually undetectable in the central conduction system. In the human foetal heart Cx43 was virtually undetectable in the atria but was the predominant connexin in the ventricles. We conclude that, at least in some key aspects, the pattern of connexin expression in the developing mouse heart parallels that found in the human embryonic heart.
Similar content being viewed by others
References
Goodenough DA, Goliger JA, Paul DL: Connexins, connexons, and intercellular communication. Annu Rev Biochem 65: 475-502, 1996
Yamasaki H, Naus CCG: Role of connexin genes in growth control. Carcinogenesis 17: 1199-1213, 1996
Lo CW: The role of gap junction membrane channels in development. J Bioenerg Biomembr 28: 379-385, 1996
Gros DB, Jongsma HJ: Connexins in mammalian heart function. BioEssays 18: 719-730, 1996
Willecke K, Eiberger J, Degen J, Eckardt D, Romualdi A, Gueldenagel M, Deutsch U, Soehl G: Structural and functional diversity of connexin genes in the mouse and human genome. Biol Chem 5: 725-737, 2001
Severs NJ, Rothery S, Dupont E, Coppen SR, Yeh H-I, Ko Y-S, Matsushita T, Kaba R, Halliday D: Immunocytochemical analysis of connexin expression in the healthy and diseased cardiovascular system. Microsc Res Tech 52: 301-322, 2001
Veenstra RD: Size and selectivity of gap junction channels formed from different connexins. J Bioenerg Biomembr 28: 327-337, 1996
Coppen SR, Gourdie RG, Severs NJ: Connexin45 is the first connexin to be expressed in the central conduction system of the mouse heart. Exp Clin Cardiol 6: 17-23, 2001
Coppen SR, Severs NJ, Gourdie RG: Connexin45 (α6) expression delineates an extended conduction system in the embryonic and mature rodent heart. Dev Genet 24: 82-90, 1999
Coppen SR, Dupont E, Rothery S, Severs NJ: Connexin45 expression is preferentially associated with the ventricular conduction system in mouse and rat heart. Circ Res 82: 232-243, 1998
Delorme B, Dahl E, Jarry-Guichard T, Briand JP, Willecke K, Gros D, Theveniau-Ruissy M: Expression pattern of connexin gene products at the early developmental stages of the mouse cardiovascular system. Circ Res 81: 423-437, 1997
Van Kempen MJA, Vermeulen JLM, Moorman AFM, Gros D, Paul DL, Lamers WH: Developmental changes of connexin40 and connexin43 messenger RNA. Cardiovasc Res 32: 886-900, 1996
Gourdie RG, Litchenberg WH, Eisenberg LM: Gap junctions and heart development. In: W.C. De Mello (ed). Heart Cell Communication in Health and Disease. Kluwer, 1998, pp 19-44
Alcolea S, Theveniau-Ruissy M, Jarry-Guichard T, Marics I, Tzouanacou E, Chauvin JP, Briand JP, Moorman AF, Lamers WH, Gros DB: Down-regulation of connexin 45 gene products during mouse heart development. Circ Res 84: 1365-1379, 1999
White TW, Paul DL: Genetic diseases and gene knockouts reveal diverse connexin functions. Annu Rev Physiol 61: 283-310, 1999
Elfgang C, Eckert R, Lichtenberg-Fraté H, Butterweck A, Traub O, Klein RA, Hülser DF, Willecke K: Specific permeability and selective formation of gap junction channels in connexin-transfected HeLa cells. J Cell Biol 129: 805-817, 1995
Ko Y-S, Coppen SR, Dupont E, Rothery S, Severs NJ: Regional differentiation of desmin, connexin43 and connexin45 expression patterns in rat aortic smooth muscle. Arterioscler Thromb Vasc Biol 21: 355-364, 2001
Vozzi C, Dupont E, Coppen SR, Yeh H-I, Severs NJ: Chamber-related differences in connexin expression in the human heart. J Mol Cell Cardiol 31: 991-1003, 1999
Kumai M, Nishi K, Nakamura K, Takeda N, Suzuki M, Shibata Y: Loss of connexin45 causes a cushion defect in early cardiogenesis. Development 127: 3501-3512, 2000
Krüger O, Plum A, Kim J-S, Winterhager E, Maxeiner S, Hallas G, Kirchhoff S, Traub O, Lamers WH, Willecke K: Defective vascular development in connexin 45-deficient mice. Development 127: 4179-4193, 2000
Dupont E, Ko YS, Rothery S, Coppen SR, Baghai M, Haw M, Severs NJ: The gap-junctional protein, connexin40, is elevated in patients susceptible to post-operative atrial fibrillation. Circulation 103: 842-849, 2001
Kirchhoff S, Nelles E, Hagendorff A, Krüger O, Traub O, Willecke K: Reduced cardiac conduction velocity and predisposition to arrhythmias in connexin40-deficient mice. Curr Biol 8: 299-302, 1998
Simon AM, Goodenough DA, Paul DL: Mice lacking connexin40 have cardiac conduction abnormalities characteristic of atrioventricular block and bundle branch block. Curr Biol 8: 295-298, 1998
Plum A, Hallas G, Magin T, Dombrowski F, Hagendorff A, Schumacher B, Wolpert C, Kim J-S, Lamers WH, Evert M, Meda P, Traub O, Willecke K: Unique and shared functions of different connexins in mice. Curr Biol 10: 1083-1091, 2000
Reaume AG, De Sousa PA, Kulkarni S, Langille BL, Zhu D, Davies TC, Juenja SC, Kidder GM, Rossant J: Cardiac malformation in neonatal mice lacking connexin43. Science 267: 1831-1834, 1995
Huang GY, Wessels A, Smith BR, Linask KK, Ewart JL, Lo CW: Alteration in connexin 43 gap junction gene dosage impairs conotruncal heart development. Dev Biol 198: 32-44, 1998
Huang GY, Cooper ES, Waldo K, Kirby ML, Gilula NB, Lo CW: Gap junction-mediated cell-cell communication modulates mouse neural crest migration. J Cell Biol 143: 1725-1734, 1998
Guerrero PA, Schuessler RB, Davis LM, Beyer EC, Johnson CM, Yamada KA, Saffitz JE: Slow ventricular conduction in mice heterozygous for connexin43 null mutation. J Clin Invest 99: 1991-1998, 1997
Morley GE, Vaidya D, Samie FH, Lo C, Delmar M, Jalife J: Characterization of conduction in the ventricles of normal and heterozygous Cx43 knockout mice using optical mapping. J Cardiovasc Electrophysiol 10: 1361-1375, 1999
Gutstein DE, Morley GE, Tamaddon H, Vaidya D, Schneider MD, Chen J, Chien KR, Stuhlmann H, Fishman GI: Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res 88: 333-339, 2001
Coppen SR, Severs NJ: Diversity of connexin expression patterns in the atrioventricular node: Vestigial consequence or functional specialization. J Cardiovasc Electrophysiol 13: 625-626, 2002
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Coppen, S.R., Kaba, R.A., Halliday, D. et al. Comparison of connexin expression patterns in the developing mouse heart and human foetal heart. Mol Cell Biochem 242, 121–127 (2003). https://doi.org/10.1023/A:1021150014764
Issue Date:
DOI: https://doi.org/10.1023/A:1021150014764