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Circulation Research. 2005;96:809-811
doi: 10.1161/01.RES.0000165653.83279.20
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(Circulation Research. 2005;96:809.)
© 2005 American Heart Association, Inc.

Editorials

Understanding Conduction System Development

A Hop, Skip and Jump Away?

Glenn I. Fishman

From the Leon H. Charney Division of Cardiology, New York University School of Medicine, New York.

Correspondence to: Glenn I. Fishman, M.D. Leon H. Charney Division of Cardiology New York University School of Medicine 550 First Avenue, OBV A615 New York, New York, USA 10016 Tel: 212-263-3967 Fax: 212-263-3972 E-mail glenn.fishman{at}med.nyu.edu



See related article, pages 898–903


Key Words: cardiac conduction system • homeodomain only protein • transcription factors

In the late 1800s, W.H. Gaskell demonstrated that impulse propagation from the atrium to the ventricle of the tortoise heart reflected conduction along myocardial tissue rather than nerve tissue.1 A decade later, Stanley Kent proposed, incorrectly as it turns out, that multiple muscular connections normally link the atria and ventricles of mammals,2 but it was not until the remarkably detailed report almost 100 years ago by Sunao Tawara, working in the laboratory of Ludwig Aschoff in Germany, that the histological identification and characterization of the atrioventricular node, the penetrating bundle of His, the left and right bundle branches and Purkinje fiber network was established.3 The notion that aberrant conduction between atria and ventricles might account for rhythm disturbances was first proposed in 1930, when the renowned American cardiologist Paul Dudley White and the English physicians John Parkinson and Louis Wolff reported on a series of patients with a short PR interval and apparent bundle branch block who were prone to paroxysmal tachycardia.4

During the past decade, there has been growing realization of the importance of diseases involving the cardiac conduction system (CCS), maladies that are now known to reflect diverse pathologic mechanisms including not only post-operative complications following surgical repair of congenital heart defects, but also immunological and metabolic disorders, degenerative processes and most recently - transcriptional dysregulation.5–9

Classically, the adult CCS is thought to encompass cells of the sinoatrial node, the atrioventricular node, common bundle of His, left and right bundle branches and distal Purkinje fiber network.10,11 Whether other "specialized cells" exist, such as those in the pulmonary vein musculature or as discrete tracts within the atria, and whether such cells are developmentally related to the more classic components of the CCS remains uncertain and controversial.12–15 Undoubtedly, this controversy reflects a transition from definitions based on morphological criteria using histological tools pioneered by a succession of eminent histologists, to molecular criteria based primarily on patterns of gene expression. This controversy is especially important in the context of development, as classic histological features used to define elements of the ventricular CCS may not be applicable in embryonic stages.16

In contrast to the remarkable pace of progress defining the transcriptional regulation of cardiac development,17–19 our understanding of the specification, patterning, maturation and maintenance of the CCS has lagged behind. However, recent work has identified several potential signaling molecules implicated in the formation of the CCS, including endothelin, neuregulin, Wnts and BMPs.20–27 Additionally, a series of papers has focused increasing attention specifically on the transcriptional regulation of the conduction system network. Interestingly, a number of transcription factors indispensable for critical stages in early heart formation also appear to play distinct roles in the patterning and/or maintenance of cells of the conduction system network. Indeed, this duality of function has at times initially obscured the phenotypic consequences of transcriptional dysregulation. For example, homozygous mice harboring inactivating mutations of the Nkx2–5 gene demonstrate defects in looping morphogenesis and embryonic lethality at 9 to 10 days post-coitum; yet not until human genetic studies implicated Nkx2–5 mutations in conduction system disease did more detailed experimentation reveal transient preferential expression of Nkx2–5 in the atrioventricular conduction system, as well as its specific requirement in the recruitment and/or survival of this subset of cells.6,28–30 Similarly, mutations in the Tbx-5 gene were identified as the cause of Holt-Oram syndrome eight years ago and initial studies of its expression pattern within the developing heart was reported soon thereafter.5,31 Yet only very recently was the preferential expression of Tbx-5 within the central conduction system appreciated and its role in the maturation of the AV node and pattering of the bundle branches clarified.32

In this issue of Circulation Research, yet another transcription factor with an apparent dual role in heart formation and function has been characterized.33 Hop (homeodomain only protein) is an unusual protein that contains a homeodomain similar to Hox transcription factors but fails to directly bind DNA.34,35 Hop functions downstream of Nkx2–5 and appears to play a pivotal role in the regulation of myocyte growth and proliferation through antagonism of serum response factor activity, in a process involving recruitment of histone deacetylase activity.36 The Hop transcript is strongly expressed throughout the developing myocardium prior to 11.5 days post-coitum in the mouse heart and subsequently becomes restricted to the trabecular zone. Targeted deletion leads to an incompletely penetrant phenotype, with approximately half of Hop-deficient embryos developing myocardial wall thinning, heart failure and death between 9.5 and 10.5 days post-coitum, whereas others survive embryogenesis but go on to develop a hypercellular phenotype.34,35

Using a knock-in strategy to place a lacZ reporter gene under the transcriptional control of the Hop locus, Ismat and colleagues now report that in the adult heart expression of Hop is restricted to the AV node, His bundle and bundle branches, as well as more broadly within the atria.33 Although Hop functions downstream of Nkx2–5, unlike the case with Nkx2–5-deficiency, the AV node and His bundle do not appear atrophic in surviving homozygous Hop mutant mice, suggesting a primary role in the maintenance of CCS function, rather than in CCS specification or patterning. The putative role of Hop as a regulator of the balance between proliferation and differentiation is intriguing, inasmuch as Tbx-5, now also known to be preferentially expressed in the CCS, is thought to negatively regulate proliferation37 and cells of the CCS appear to have diminished proliferative activity during embryonic and fetal stages compared with working cardiomyocytes.25,38

Ismat et al also examined the functional consequences of Hop deficiency in surviving adult mice.33 Programmed electrical stimulation revealed several functional abnormalities including increased P-wave duration, minor prolongation of the AH interval, prolonged atrial refractoriness, widening of the QRS complex and prolongation of the HV interval. These electrophysiological findings are similar, but not identical to those found in connexin40-deficient mice39–42 and indeed expression of this gap junction protein, which is a well-characterized transcriptional target of Nkx2–5 as well as Tbx-5,43 was markedly reduced in the atria, AV node, His bundle and bundle branches of Hop mutant mice.

A growing number of transcription factors with potential roles in conduction system formation and function have been identified, including additional T-box family members such as Tbx-3 and Tbx-2,19,44,45 the vertebrate muscle segment related homeobox factor Msx-246,47 and the SP1-related factor HF-1b.48 Moreover, increasingly sophisticated strategies to unambiguously identify cells of the conduction system and determine their unique patterns of gene expression and function continue to evolve.49–51 Ismat et al add to our growing understanding of conduction system development, but unraveling this complex process is still not a hop, skip and jump away.


*    Acknowledgments
 
This work was supported by NIH Grants HL64757 and HL30557 and a Burroughs-Wellcome Fund Clinical-Scientist Award in Translational Research.


*    Footnotes
 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.


*    References
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 *References
 

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Related Article:

Homeobox Protein Hop Functions in the Adult Cardiac Conduction System
Fraz A. Ismat, Maozhen Zhang, Hyun Kook, Bin Huang, Rong Zhou, Victor A. Ferrari, Jonathan A. Epstein, and Vickas V. Patel
Circ. Res. 2005 96: 898-903. [Abstract] [Full Text] [PDF]




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