© 1997 American Heart Association, Inc.
Articles |
Protean Patterns of Gene Expression in the Heart Conduction System
Correspondence to Dr Stefano Schiaffino, Department of Biomedical Sciences, Viale G. Colombo 3, 35121 Padova, Italy. E-mail schiaffi{at}civ.bio.unipd.it
Key Words: heart conduction tissue • gene regulation • myofibrillar protein • editorial
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Introduction |
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 Top Introduction References |
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The heart conduction system consists of different muscle cell populations specialized for the generation and propagation of the electrical impulse and responsible for the coordinated activation of atrial and ventricular myocardium. Cells present in the SA and AV nodes are generally smaller than ordinary myocardial cells and appear similar to embryonic cardiomyocytes with respect to morphology and electrophysiological properties, eg, slow conduction velocity. In contrast, the Purkinje cells of the ventricular conduction system are often larger than ordinary myocardial cells and are characterized by fast conduction velocity. There are considerable species variations in the morphology of conduction system cells and further heterogeneity within the nodes and the peripheral Purkinje fibers. Immunocytochemical and in situ hybridization analyses have added a new dimension of complexity by showing that heart conduction system cells express markers typical of skeletal muscle, in addition to markers typical of cardiac muscle. In the chicken, ventricular Purkinje cells contain a slow skeletal MHC, which is not present in the ordinary myocardium.1 2 In the adult rat heart, AV node cells contain slow skeletal TnI transcripts, whereas ordinary cardiomyocytes contain cardiac TnI transcripts.3 An MHC isoform immunologically similar to that expressed in embryonic skeletal muscle has been detected in bovine and rat nodal cells.4 5
In this issue of Circulation Research, Alyonycheva et al6 report that another skeletal muscle protein, thick-filament MyBP-H, is expressed in ventricular Purkinje cells but not in ordinary myocardial cells of the chicken heart. MyBP-H, like MyBP-C, belongs to a family of myofibrillar proteins with a modular structure, characterized by the presence of repetitive domains homologous to immunoglobulin or fibronectin type III repeats (see Reference 77 for review). MyBP-H contains two immunoglobulin and two fibronectin repeats arranged like those present in the carboxy-terminal region of MyBP-C.8 There are three MyBP-C genes, coding for the fast skeletal, slow skeletal, and cardiac isoforms, whereas at present there is evidence for a single MyBP-H gene, which was thought to be expressed exclusively in skeletal muscle. On the basis of protein and RNA studies, Alyonycheva et al6 show that the MyBP-H present in Purkinje cells is indistinguishable from that present in skeletal muscle.
How can we explain the presence of skeletal muscle proteins in heart
conduction system cells? One possibility is that this finding reflects
the promiscuous pattern of gene expression seen in developing muscle
tissues. Multiple myofibrillar protein genes from the same gene family
are often coexpressed in cardiac and skeletal muscle during embryonic
development and are subsequently downregulated in one tissue or the
other. For example, rat atria and ventricles initially express slow
skeletal TnI and then start to express cardiac TnI, and the slow
skeletal isogene is completely downregulated during early postnatal
development.3 This switch does not occur in nodal tissues,
in which slow skeletal TnI remains the predominant isoform. In this
case, the presence of the skeletal muscle protein simply reflects the
persistence of an embryonic-like phenotype in nodal cells. Slow
skeletal TnI is in fact an embryonic marker rather than a skeletal
muscle marker. On the other hand, an inverse switch from a cardiac to a
skeletal muscle gene occurs with the slow skeletal MHC, which is absent
in the chicken embryonic heart and is induced in differentiating
Purkinje cells at later developmental stages.2 In this
case, the switch appears to reflect a real process of differentiation
of Purkinje cells. It remains to be established whether MyBP-H behaves
like slow skeletal TnI or like slow skeletal MHC, in other words,
whether the developmental switch occurs in Purkinje cells or in the
ordinary myocardium. This will require analysis of
early embryonic development, since by embryonic day 18 MyBP-H is
already selectively expressed in the ventricular Purkinje
fibers of the chicken heart.6 The factors implicated in
the activation of skeletal muscle genes in the heart conduction system
are not known. The regulatory genes of the skeletal muscle–specific
MyoD gene family are not expressed in the conduction tissue. However,
skeletal muscle and Purkinje fibers may share regulatory mechanisms, as
suggested by the finding that a segment 
1 kb of the 5' flanking
region of the desmin gene directs expression of a reporter gene in
skeletal muscle fibers and in the cardiac conduction tissue but not in
the working myocardium.9
The presence of skeletal muscle markers is only one aspect of the atypical pattern of gene expression in heart conduction system cells. An even more striking and unorthodox feature of these cells is the presence of neural markers. The best characterized neural marker is the neurofilament M subunit present in the conduction system cells of the rabbit heart.10 A cDNA corresponding to neurofilament M has been recently isolated from a cDNA library of rabbit SA node, and the corresponding transcript has been detected in rabbit nodal myocytes.11 Other neural markers have been demonstrated in conduction system cells by histochemical and immunocytochemical techniques.12 A neuronal type I–like Na+ channel has been recently detected in the newborn rabbit sinoatrial node.13 The significance of nerve-specific gene expression in the heart conduction system is unknown. It has been suggested that some myocyte populations of the heart conduction system may have a neural crest origin10 ; however, this hypothesis is not supported by direct evidence. On the other hand, neural crest cells may indirectly influence conduction tissue differentiation. As Alyonycheva et al6 point out in their article, there is evidence that neural crest–derived cells affect the development of the coronary arteries, and it is likely that local signals from coronary arteries and/or associated neural crest derivatives may be implicated in the differentiation of chicken ventricular Purkinje cells.
Definitive conclusions about the origin of the heart conduction system can only be provided by cell lineage analysis using quail-chick chimeras, retroviral labeling, or stain injection techniques. Mikawa and Fischman (see reference 14 for review) have pioneered a direct retroviral tagging approach for cell lineage analysis in the developing chicken heart. A major result of these studies has been the finding that clones derived from single cardiomyocytes after retroviral tagging at embryonic day 3, ie, at a time when neural crest cells have not yet invaded the heart, contain both Purkinje fibers and ordinary myocytes, indicating that these two cell populations arise from the same myogenic precursors.15 However, cells in SA and AV nodes and AV bundles were never labeled in these studies; therefore, the central conduction system cells must have a different origin. It has been suggested that nodal cells derive directly from the embryonic "primary myocardium," which precedes the formation of the working myocardium chambers and shares with nodal tissues several properties, including slow conduction and coexpression of multiple myofibrillar isoforms.16
The problem of gene regulation in the heart conduction system, including the puzzle of the protean patterns of gene expression, is closely related to the identification of the genetic pathways that control heart morphogenesis and chamber specification. Our understanding of the molecular genetics of heart development is rapidly progressing17 and will give further impetus to promote a molecular biology of the heart conduction system. Major advances can be expected from multiple directions, including the screening of cDNA libraries from nodal tissues,11 the study of transgenic mice showing regional variations in transgene expression,9 and the characterization of genes responsible for heart conduction defects.18 19
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Selected Abbreviations and Acronyms |
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editor or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. Sartore S, Pierobon Bormioli S, Schiaffino S. Immunohistochemical evidence for myosin polymorphism in the chicken heart. Nature.. 1978;274:82-83.[Medline] [Order article via Infotrieve]
2.
Gonzalez-Sanchez A, Bader D. Characterization
of a myosin heavy chain in the conductive system of the adult and
developing chicken heart. J Cell Biol.. 1985;100:270-275.
3. Gorza L, Ausoni S, Merciai N, Hastings KEM, Schiaffino S. Regional differences in troponin I isoform switching during rat heart development. Dev Biol.. 1993;156:253-264.[Medline] [Order article via Infotrieve]
4.
Gorza L, Sartore S, Thornell LE, Schiaffino S.
Myosin types and fiber types in cardiac muscle, III: nodal conduction
tissue. J Cell Biol.. 1986;102:1758-1766.
5. Gorza L, Saggin L, Sartore S, Ausoni S. An embryonic-like myosin heavy chain is transiently expressed in nodal conduction tissue of the rat heart. J Mol Cell Cardiol.. 1988;20:931-941.[Medline] [Order article via Infotrieve]
6.
Alyonycheva T, Cohen-Gould L, Siewert C, Fischman DA,
Mikawa T. Skeletal muscle–specific myosin binding protein-H is
expressed in Purkinje fibers of the cardiac conduction system.
Circ Res.. 1997;80:665-672.
7.
Schiaffino S, Reggiani C. Molecular diversity
of myofibrillar proteins: gene regulation and functional
significance. Physiol Rev.. 1996;76:371-423.
8.
Vaughan KT, Weber FE, Einheber S, Fischman DA.
Molecular cloning of chicken myosin-binding protein (MyBP) H (86-kDa
protein) reveals extensive homology with MyBP-C (C-protein) with
conserved immunoglobulin C2 and fibronectin type III motifs.
J Biol Chem.. 1993;268:3670-3676.
9. Li Z, Marchand P, Humbert J, Babinet C, Paulin D. Desmin sequence elements regulating muscle-specific expression in transgenic mice. Development.. 1993;117:947-959.[Abstract]
10. Gorza L, Schiaffino S, Vitadello M. Heart conduction tissue: a neural crest derivative? Brain Res. 1988;457:360-366.[Medline] [Order article via Infotrieve]
11. Vitadello M, Vettore S, Lamar E, Chien KR, Gorza L. Neurofilament M mRNA is expressed in the conduction system myocytes of the developing and adult rabbit heart. J Mol Cell Cardiol.. 1996;28:1833-1844.[Medline] [Order article via Infotrieve]
12. Gorza L, Vettore S, Vitadello M. Molecular and cellular diversity of heart conduction system myocytes. Trends Cardiovasc Med.. 1994;4:153-159.
13. Baruscotti M, Westenbroek R, Catteral WA, DiFrancesco D, Robinson RB. The newborn rabbit sinoatrial node expresses a neuronal type I–like Na+ channel. J Physiol.1997;496:641-648.
14. Mikawa T, Fischman DA. The polyclonal origin of myocyte lineages. Ann Rev Physiol.. 1996;58:509-521.[Medline] [Order article via Infotrieve]
15. Gourdie RG, Mima T, Thompson RP, Mikawa T. Terminal diversification of the myocyte lineage generates Purkinje fibers of the cardiac conduction system. Development.. 1995;121:1423-1431.[Abstract]
16. Moorman A, Lamers WH. Molecular anatomy of the developing heart. Trends Cardiovasc Med.. 1994;4:257-264.
17. Olson EN, Srivastava D. Molecular pathways controlling heart development. Science.. 1996;272:671-676.[Abstract]
18. Stainier DYR, Fouquet B, Chen J-N, Warren KS, Weinstein BM, Meiler SE, Mohideen MPK, Neuhauss SCF, Solnica-Krezel L, Schier AF, Zwartkruis F, Stemple DL, Malicki J, Driever W, Fishman MC. Mutations affecting the formation and function of the cardiovascular system in the zebrafish embryo. Development.. 1996;123:285-292.[Abstract]
19. Chen J-N, Haffter P, Odenthal J, Vogelsang E, Brand M, van Eeden FJM, Furutani-Seiki M, Granato M, Hammerschmidt M, Heisenberg C-P, Jiang Y-J, Kane DA, Kelsh RN, Mullins MC, Nusslein-Volhard C. Mutations affecting the cardiovascular system and other internal organs in zebrafish. Development.. 1996;123:293-302.[Abstract]
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