Download Unveiling the transcriptional control of the developing cardiac

Cardiovascular Research 62 (2004) 444 – 446
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Editorial
Unveiling the transcriptional control of the developing cardiac
conduction system
Diego Franco *
Department of Experimental Biology, Faculty of Health and Experimental Sciences, University of Jaén, 23071 Jaén, Spain
Received 4 March 2004; accepted 10 March 2004
The development of the heart is a fascinating process.
The heart starts out as a straight tube that subsequently
bends to the right and forms an embryonic heart with
prospective atrial and ventricular chambers [1]. Soon after,
septation is initiated and the atrial and ventricular chambers
are separated into left and right components, configuring a
four-chambered organ with synchronous contraction. Distinct cell lineages are involved in these processes and their
respective morphogenetic contributions are well described.
Over the last decade, a turning point has taken place in the
field of cardiovascular development since the first cardiacenriched transcription factors were discovered. Soon after,
the generation of targeted mutations led to a wide range of
cardiac phenotypes that has progressively enriched our
understanding of cardiac (dis)morphogenesis (for a review,
see Ref. [2]). Molecular interactions between different
transcriptional regulators have been relatively accurately
deciphered with respect to the major morphogenetic cardiac
events. Interestingly, whereas there was an initial hope that a
master myocardial gene would be discovered that eventually
would be the key regulator of cardiac differentiation, it is
now clear that the regulation of the myocardial phenotype is
a complex system in which many players are involved.
The advent of tissue-specific molecular markers has
greatly allowed a more comprehensive understanding of
cardiac development. In fact, the coupling of gene
expression profile during cardiac development to other
functional molecular biological techniques has permitted a
more accurate understanding of cardiac (dis)morphogenesis [3]. Gene expression experiments in the developing
heart already pointed out that the myocardium is rather
heterogeneous (for a review, see Ref. [4]). Detailed
studies using transgenic mouse models as well as endogenous gene expression profiling have demonstrated a
progressive complexity of the myocardial domains as
* Tel.: +34-95-3002763; fax: +34-95-3012141.
E-mail address: [email protected] (D. Franco).
well as their transcriptional pathways. In fact, in the
early tubular heart (mouse E8.0), only homogeneous or
gradient expression patterns are observed, whereas in the
embryonic heart (mouse E10.5), at least five different
regions can be delimited [4]. Such myocardial complexity
is even more extensive in the adult heart, as recently
described for the atrial chambers [5].
It is interesting to realize, nonetheless, that in the adult
heart, the myocardium has been conventionally divided in
two types, the fast-contracting chamber atrial and ventricular myocardium and the pace-making conducting cardiac
conduction system (CCS) [6]. The existence of such a
special type of myocardial cells is specifically required for
the synchronous contraction of the atrial and ventricular
chambers. The CCS in the adult heart can be divided into
different components based on their molecular and electrophysiological characteristics [6,7]. Surprisingly, although
the morphogenetic events that allow the formation of a
four-chambered heart from a progenitor myocardial cell
pools, including the morphological basis of the synchronous
cardiac conductive properties, have been analyzed and
carefully described for several decades, there is still some
overt discussion about the developmental origin of the
specialized CCS. It remains unknown whether the CCS is
derived from the developing myocardium or else from an
extracardiac origin [6,8]. It was first proposed that discrete
areas of the atrioventricular canal myocardium, characterized by a glycogen-rich content, were the precursors of the
atrioventricular node in the mouse [9]. Soon thereafter, a
novel molecular marker, Gln2, allowed the prospective
progenitor cells of the atrioventricular bundle to be traced
back in humans [10]. However, the finding that some
neurofilament markers were specifically expressed in the
cardiac conduction system in the rabbit suggested that the
neural crest cells might contribute to the development of this
tissue [11].
Nowadays, a bulk of circumstantial evidence, mainly
sustained by similar gene expression profiles of discrete
0008-6363/$ - see front matter D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cardiores.2004.03.012
D. Franco / Cardiovascular Research 62 (2004) 444–446
myocardial segments in the developing heart, clearly supports a myocardial origin of the CCS [6,12]. In addition, a
number of experiments, such as cardiac neural crest ablation
and retroviral cell fate experiments, have failed to obtain any
direct evidence of a substantial contribution to the function
and/or formation of the CCS from the cardiac neural crest
cells [13].
At present, only two transcription factors (Nkx2.5 and
Tbx5) have been described to play a role in cardiac
conduction system function [14,15]. Nonetheless, their
role during CCS development remains to be clarified.
In this issue of Cardiovascular Research, Hoogaars/Tessari et al. [16] have uncovered a novel molecular marker
that delineates the majority of the murine cardiac conduction system. The authors unveil the cardiac expression
profile of a T-box family transcription factor, Tbx3,
which is highly enriched in the fully developed CCS.
Furthermore, the developmental profile of Tbx3 expression is enriched in those putative embryonic myocardial
regions that have been previously proposed as early
contributors of the ventricular conduction tissue [7],
supporting a myocardial origin of the CCS.
In addition, since Tbx3 is a transcription factor with
DNA binding capabilities, these data give novel insights
about the transcriptional mechanisms governing the development of the CCS. Interestingly, Hoogaars/Tessari et al.
[16] provide convincing evidence of a putative mechanism
by which the cardiac conduction system might escape from
a working myocardium phenotype by preventing the expression of putative chamber myocardial markers such as
atrial natriuretic factor. However, there are some caveats to
this model that would require a refinement of our understanding on how Tbx3 acts in the developing heart. Firstly,
Tbx3 is not expressed exclusively in the myocardial boundaries of the prospective cardiac conduction system components, but it also expands into the atrioventricular cushions
[16]. The role of Tbx3 in the mesenchymal cushions has yet
to be explored. Secondly, there are additional myocardial
Tbx3-expressing areas in the fetal and adult heart that might
be considered as remnants of the embryonic slow conducting areas, as suggested by the authors. However, the
putative repressor role of Tbx3 in these areas becomes
unclear, especially concerning the novel finding of internodal tracts between the sinoatrial and atrioventricular
nodes [16]. Thirdly, and more intriguingly, Tbx3 null
mutant mice lack an overt cardiac conduction system
phenotype [17]. A scenario might be that a lack of Tbx3
might be compensated by Tbx2, which is also transiently
expressed in the conduction system and also has a repressor
DNA binding activity [18]. At present, addressing this point
is compromised due to the early embryonic lethality
reported in the Tbx3 mutant mice [17], which is earlier
than the cardiac conduction system can be firstly traced
morphologically. In this context, it is important to realize
that Tbx5 is also expressed in the developing cardiac
conduction system and, furthermore, that it is essential for
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the correct morphogenesis of the conduction system [15].
Thus, from previous data and those reported in this issue by
Hoogaars/Tessari et al. [16], the relevance of the T-box
transcription factors in the development of the conduction
system in the mouse is emerging. The generation of conditional null mutants will provide a future framework for the
detailed understanding of the transcription factors of the Tbox family members that are expressed in the developing
myocardium. In the same line of thinking, the emergence of
new early molecular markers that can finely delineate the
cardiac conduction system will be an important step forward
for our understanding of the transcriptional mechanisms
governing the formation of the cardiac conduction system.
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