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Transcriptional regulation of cardiac conduction system development2004 FASEB cardiac conduction system minimeeting Washington DC.

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THE ANATOMICAL RECORD PART A 280A:1036 –1045 (2004)
Transcriptional Regulation of Cardiac
Conduction System Development: 2004
FASEB Cardiac Conduction System
Minimeeting, Washington, DC
BRETT S. HARRIS,1,2* PATRICK Y. JAY,3 MARY S. RACKLEY,2,4
SEIGO IZUMO,5 TERRENCE X. O’BRIEN,2,4 AND ROBERT G. GOURDIE1
1
Department of Cell Biology and Anatomy, Medical University of South Carolina,
Charleston, South Carolina
2
Gazes Cardiac Research Institute, Medical University of South Carolina,
Charleston, South Carolina
3
Developmental Biology Unit, Department of Pediatrics, Washington University
School of Medicine, St. Louis, Missouri
4
Medical Research Service, Ralph H. Johnson Department of Veteran Affairs
Medical Center, Medical University of South Carolina, Charleston, South Carolina
5
Cardiology Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts
ABSTRACT
The development of the complex network of specialized cells that form the atrioventricular
conduction system (AVCS) during cardiac morphogenesis occurs by progressive recruitment
within a multipotent cardiomyogenic lineage. Understanding the molecular control of this developmental process has been the focus of recent research. Transcription factors representative of
multiple subfamilies have been identified and include members of zinc-finger subfamilies
(GATA4, GATA6 HF-1b), skeletal muscle transcription factors (MyoD), T-box genes (Tbx5), and
also homeodomain transcription factors (Msx2 and Nkx2.5). Mutations in some of these transcription factors cause congenital heart disease and are associated with cardiac abnormalities,
including deficits within the AVCS. Mouse models that closely phenocopy known human heart
disease provide powerful tools for the study of molecular effectors of AVCS development. Indeed,
investigations of the Nkx2.5 haploinsufficient mouse have shown that peripheral Purkinje fibers
are significantly underrepresented. This piece of data corroborates our previous work showing in
chick, mouse, and humans that Nkx2.5 is elevated in the differentiating AVCS relative to
adjacent working ventricular myocardial tissues. Using the chick embryo as a model, we show
that this elevation of Nkx2.5 is transient in the network of conduction cells comprising the
peripheral Purkinje fiber system. Functional studies using defective adenoviral constructs, which
disrupt the normal variation in level of this gene, result in perturbations of Purkinje fiber
phenotype. Thus, the precise spatiotemporal regulation of Nkx2.5 levels during development may
be required for the progressive emergence of gene expression patterns specific to differentiated
Purkinje fiber cells. Published 2004 Wiley-Liss, Inc.†
Key words: heart conduction system; Nkx2-5; Purkinje fibers; development;
atrioventricular block
The atrioventricular conduction system (AVCS) is essential for the coordination of normal contractile cycles of
the heart (Pennisi et al., 2002; Gourdie et al., 2003; Moorman and Christoffels, 2003). The cardiac activation is
initiated in the sinoatrial node (SAN) located at the junction of the sinus venosus and right atrium and spreads
through the atria to the atrioventricular junction. Here,
activation coalesces into a single specialized central structure, the atrioventricular node (AVN). The AVN acts as a
delay generator and forms the gateway to a fast conduction tissue pathway that networks through the ventricles.
From the AVN, fast conduction propagates through a sinPublished 2004 WILEY-LISS, INC. †This article is a U.S. Government
work and, as such, remains in the public domain of the United States of
America.
Seigo Izumo’s present address is Novartis Institutes for Biomedical Research, Cambridge, MA.
*Correspondence to: Brett S. Harris, Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425. Fax: 843-792-0664. E-mail: harrisbs@musc.edu
Received 3 June 2004; Accepted 18 June 2004
DOI 10.1002/ar.a.20101
Published online 14 September 2004 in Wiley InterScience
(www.interscience.wiley.com).
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TRANSCRIPTIONAL REGULATION
TABLE 1. Transcription factors identified within the atrioventricular conduction system*
Transcription
factor family
Zinc-finger
bHLH
T-box
Homeodomain
Transcription
factor name
Cardiac
expression
Conduction
tissue
GATA4
GATA6
HF-1b
MyoD
Tbx-5
Msx2
PCM, WM
PCM
RA, WM
Nkx2-5
PCM, WM
PFs
AVN, His
AVN, His, PFs
His, PFs
AVN, His
AVN, His, LBB,
RBB
AVN, His, LBB,
RBB, PFs
PCM
WM
Organism
Stage
Human, mouse, chicken
Mouse
Human, mouse
Chicken
Human, mouse, chicken
Mouse, chicken
E9 adult
E9
E17.5
E16 adult
HH14
Human, mouse, chicken
10.1 W E9 HH24-P5
*PCM, precardiac mesoderm; WM, working myocardium; AVN, atrioventricular node; His, His bundle; LBB, left bundle
branch; RBB, right bundle branch; Pfs, Purkinje fibers; W, weeks of human gestation; E, embryonic day; HH, Hamburger and
Hamilton staging of the chick.
gle His bundle located at the crest of the interventricular
septum, which bifurcates into the left and right bundle
branches, directing signals to the left and right ventricles,
respectively. These large conduction bundles then expand
into an extensive network of peripheral Purkinje fibers
that terminate onto the working cardiomyocytes of the
ventricles.
Previously, we have shown that the elaboration of the
AVCS during cardiac morphogenesis occurs by a process of
progressive recruitment within a multipotent cardiomyogenic lineage, rather than from proliferative outgrowth of
already differentiated conduction cells (Gourdie et al.,
1995; Cheng et al., 1999). Our knowledge of the molecular
cues that determine the development of this complex set of
specialized cardiac tissues has undergone significant advances in the last decade. The discovery of specific transcription factors present within and important for conduction cell development is ongoing (Bruneau, 2002; Myers
and Fishman, 2003). Transcription factors representative
of multiple subfamilies have been identified and include
members of zinc-finger subfamilies, skeletal muscle transcription factors, T-box genes, and also homeodomain
transcription factors (Table 1). It is noteworthy that no
single transcription factor defines the entire conduction
system either spatially or temporally during development
and subsequent maturation.
ZINC-FINGER TRANSCRIPTION FACTORS
The GATA family of transcription factors is relatively
small in size, with only six vertebrate members currently
identified (Patient and McGhee, 2002). Members of this
family possess a binding domain consisting of either one or
two zinc-finger motifs coupled to a region rich in basic
residues and derive their name from the consensus sequence to which they bind, (A/T) GATA (A/G). Of the six
known vertebrate GATA transcription factors, three have
been implicated in cardiogenesis: GATA4, -5, and -6
(Molkentin, 2000). GATA4 is expressed in the embryonic
and adult murine heart and targeted disruption results in
a lethal phenotype (Kuo et al., 1997; Narita et al., 1997).
These mice die at around embryonic day 8 due to compound abnormalities of foregut closure and heart dismorphogenesis characterized as cardiac bifida. Further significance for a cardiovascular function of this gene comes
from the finding that in humans GATA4 is located on
chromosome 8p22-23 and that deletion of this region may
cause congenital heart disease (CHD) (Bhatia et al., 1999;
Pehlivan et al., 1999). Specific mutations located within
the human GATA4 gene have now been identified in large
kindreds presenting with CHD (Garg et al., 2003). These
cardiac defects frequently include atrial septal defects
(ASDs) and, to a lesser degree, ventricular septal defects
(VSDs) and valvular abnormalities. Noticeably absent
from the recorded cardiac defects resulting from these
GATA4 mutations are abnormalities of the cardiac conduction system itself. Although GATA4 has not been described within the mammalian conduction system, its
presence has been identified within the peripheral Purkinje fibers of the adult chicken heart (Takebayashi-Suzuki et al., 2001). In this case, GATA4 mRNA has been
shown to be localized to the mature periarterial Purkinje
fibers at much higher levels than the surrounding working
myocardium. We have previously characterized an in vitro
model of conduction cell development in which dissociated
embryonic cardiomyocytes can be induced into a Purkinje
fiber phenotype by protracted exposure to the shearstress-induced cytokine, endothelin-1 (ET-1) (Gourdie et
al., 1998; Takebayashi-Suzuki et al., 2000). Using this
paradigm, it has been shown that ET-1-induced embryonic Purkinje fibers maintain expression of GATA4, leading to the suggestion that this gene may be important in
the maintenance of conduction cell phenotype (Takebayashi-Suzuki et al., 2001).
In contrast to GATA4, relatively little is known about
both GATA5 and GATA6 function, which is partly due to
the complication that these genes are involved in the early
development of endoderm. GATA5 knockout mice survive
to term but female mice experience genitourinary abnormalities (Molkentin, 2000). Surprisingly, the targeted disruption of zebrafish GATA5 (faust mutant) results in embryonic lethality due to abnormal heart development and
a reduction in cardiomyocyte numbers (Reiter et al.,
1999), similar to the GATA4 null allele in mice, suggesting
that the function of GATA4 and -5 in the fish may be
reversed to that of mouse. Inactivation of the GATA6 gene
in mice, as with GATA4, results in an embryonic lethal
phenotype but differs in that the lethality occurs even
earlier in development caused by visceral endoderm abnormalities, making study of the heart in these mutants
impossible (Morrisey et al., 1998; Koutsourakis et al.,
1999). Although GATA6 has not been shown to be present
in cells of the AVCS, an upstream enhancer element of the
proximal GATA6 promoter, derived from the chick genome, directs LacZ marker expression in a portion of these
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HARRIS ET AL.
Fig. 1. Nkx2-5 expression localizes to
the AVCS of the embryonic chick heart.
Nkx2-5 protein expression in the developing chick heart at E19 detected by immunohistochemistry with Nkx2-5 antibodies
and antibodies labeling the AVCS. A and B:
Nkx2-5 expression is present within the left
bundle branch (LBB; arrows) located in the
interventricular septum. The corresponding
phase contrast image shows the position of
the LBB (dashed lines in B). The point at
which the LBB breaks through into a subendocardial location is indicated by the arrowhead. C and D: Double immunohistochemistry shows Nkx2-5 within periarterial
Purkinje fibers (PPFs; C) and subendocardial Purkinje fibers (SPFs; D), respectively.
Here antibodies against sMHC (shown in
green; FITC) label fully differentiated conduction cells and nuclear Nkx2-5 protein
can be seen at higher levels in these specialized cells as compared to surrounding
myocardium (shown in red; TRITC).
Hoechst counterstain (blue) labels the nuclei in C. Scale bars ⫽ 100 ␮m (A, B), 50
␮m (C, D).
TRANSCRIPTIONAL REGULATION
1039
Fig. 2. Schematic diagram of Nkx2-5 detailing known human mutations. Protein schema of Nkx2-5 with
conserved regions shown as gray boxes. Overlayed are the known human NKX2-5 mutations identified in
families with congenital heart disease TN, TN domain; HB, homeodomain or DNA binding domain; NK, NK
domain; GIRAW, GIRAW sequence.
specialized cells (Davis et al., 2001). These authors have
demonstrated, using this promoter fragment termed
cGATA6, expression within the developing elements of the
central conduction system. Given the identified expression
patterns within the AVN and proximal His bundle exclusive of peripheral Purkinje fibers, the cGATA6 enhancer
has become an important tool for the transgenic analysis
of subcompartments of the atrioventricular conduction
system.
HF-1b is also a zinc-finger transcription factor family
member, but is from a different subclass from that of the
GATA family being closely related to Sp-1 from Xenopus.
The targeted disruption of the HF-1b gene by insertion of
a LacZ reporter construct has enabled the cardiac expression pattern of this gene to be analyzed in mouse (NguyenTran et al., 2000). Although HF-1b localizes to the developing working myocardium at E17, relatively high
expression levels were also noted in both central (AVN)
and peripheral (His bundle and Purkinje fibers) conduction tissues. Further immunohistochemical analysis of individual peripheral Purkinje fibers revealed that the normal patterns of connexin40 (Cx40) typically present in
these specialized cells was reduced and disorganized. The
functional consequences of such perturbations were analyzed electrophysiologicaly (using telemetry) showing that
first and second AV block together with tachycardia were
indeed present. In fact, this latter phenomenon frequently
preceded sudden cardiac death. Although abnormal conduction in the HF-1b null mice is likely due to disrupted
Cx40 patterns, it is not yet clear if there is a myocardial
component to the electrophysiology or perhaps a dysfunction of the developmental transition between Purkinje
fibers and working cardiomyocytes.
BASIC HELIX-LOOP-HELIX TRANSCRIPTION
FACTORS
The recent and intriguing finding that conduction
cells express MyoD suggests that these specialized cardiac cells share some phenotypic commonalities with
skeletal muscle (Takebayashi-Suzuki et al., 2001).
MyoD is an example of a basic helix-loop-helix transcription factor (bHLH). As this name implies, they are
characterized by a conserved DNA binding motif that
recognizes a six nucleotide DNA sequence known as an
E-box (Olson, 1993). Although this transcription factor
has not been described in cardiac muscle, it has been
shown to be present and control skeletal muscle phenotype through the transcription of proteins that are expressed similarly in both cardiac and skeletal muscle.
MyoD was detected in isolated embryonic chick cardiomyocytes and expression was further increased by
treatment of these cultures with ET-1, known to induce
Purkinje fiber phenotype in vitro (Takebayashi-Suzuki
et al., 2001). Investigation of MyoD expression in vivo
revealed that mRNA expression was detected as early
as E16 in chick periarterial Purkinje fibers from E16
while showing that MyoD protein localized to the mature periarterial Purkinje fibers present in the adult
chick heart.
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HARRIS ET AL.
Fig. 3. AdNkxHA perturbs AVCS markers in vivo. Sections of embryonic chick hearts harvested at E18 either
microinjected at E10 with AdNkxHA (A and B) or with
vehicle control (C) were immunolabeled for AVCS markers. A: Immunolabeling for HA-tag reveals abundant
Nkx2-5 overexpression within the myocardium and subendocardium of this section through the right ventricular
myocardium (shown in red; TRITC). B: A sister section to
that shown in A, immunolabeled for sMHC, shows loss of
sMHC protein within this domain of AdNkxHA-infected
tissue (shown in green FITC). Arrows indicate subendocardial region where presumptive Purkinje fibers are
found. C: Control tissue shows typical bright sMHC
staining of Purkinje fibers of the subendocardium in
age-matched control tissue (arrowheads). Scale bars ⫽
100 ␮m.
TRANSCRIPTIONAL REGULATION
Figure 4
(legend on overleaf)
1041
1042
HARRIS ET AL.
T-BOX TRANSCRIPTION FACTORS
The T-mutant is a naturally occurring genetic mutation
in mice consisting of multiple alleles present in the T/t
complex on chromosome 17 that cause a short tail phenotype (Chesley, 1935). Mutation of the T gene results in
early developmental abnormalities of the primitive streak,
which in turn causes perturbations of gastrulation with a
resulting mesodermal cell insufficiency. The T-mutant,
also known as Brachyury, was cloned in 1990, becoming
the first T-box transcription factor to be characterized
(Herrmann et al., 1990; Wilkinson et al., 1990). T-box
genes recognize and bind to a 20 base pair palindromic
DNA consensus sequence in a specific fashion, where contacts with the DNA are made in both major and minor
grooves (Muller and Herrmann, 1997; Papaioannou,
2001). This family of transcription factors is large with 20
or so members but continues to grow rapidly with the
ongoing discovery and cloning of novel T-box genes. These
transcription factors are emerging as important effectors
of normal patterning processes associated with organ development (Papaioannu, 2001). A number of T-box genes
have been identified in the developing vertebrate heart,
including Tbx1, Tbx2, Tbx3, Tbx5, Tbx12, Tbx18, and
Tbx20 (Horb and Thomsen, 1999; Carson et al., 2000;
Yamada et al., 2000; Merscher et al., 2001; Takeuchi et al.,
2003; Tanaka and Tickle, 2004). So far, in human populations, CHD has been found to be attributable to mutations within two family members of these cardiac associated T-box genes, Tbx1 and Tbx5 (Basson et al., 1997; Li et
al., 1997; Merscher et al., 2001). Tbx1 is localized to chromosome 22q11 and a 1.5 Mb deletion within this locus
may cause velocardiofacial/DiGeorge syndrome (Merscher
et al., 2001); a similar deletion in mouse also causes a
comparable phenotype to that observed in humans and
such a phenotype may be rescued in the mouse by expression of human Tbx1. A second human syndrome associated with another T-box gene is known as Holt-Oram
syndrome (HOS), an autosomal-dominant condition characterized by limb defects and congenital heart disease
(Mori and Bruneau, 2004). In this case, Tbx5 is the mutated gene and the cardiovascular abnormalities include
most commonly ASDs and, to a lesser extent, VSDs,
patent ductus arteriosus (PDA), and rarely double-outlet
right ventricle (DORV) and tetralogy of Fallot (TOF). Pertinent to this review is the finding that perturbations of
cardiac electrophysiology may also occur, indicative of abnormalities localizing to the conduction system (Basson et
al., 1994). To date, some 37 Tbx5 mutations have been
identified and the majority result in truncated proteins,
which may be nonfunctional, indicating that the disease
state is likely due to Tbx5 haploinsufficiency. A mouse
model of Tbx5 haploinsufficiency has been generated,
Fig. 4. Nkx.2-5 haploinsufficiency causes a reduction in Purkinje
fiber number. Peripheral Purkinje fibers are underrepresented in Nkx2-5
heterozygous mice. Immunohistochemistry was carried out on multiple
short-axis sections from 3-month-old wild-type and Nkx2-5 heterozygous mouse hearts. Confocal images of the right ventricle and surrounding myocardium are shown labeled with antibodies to Cx40 in red as
punctuate staining, in both wild-type (A) and Nkx2-5 ⫹/⫺ tissue (B). The
extent and distribution of Cx40 labeling in the Nkx2-5 ⫹/⫺ myocardium
(B) is considerably less when compared to the wild type (A). C and D:
which closely phenocopies the human conditions detailed
above, including the abnormal cardiac electrophysiology
(Bruneau et al., 2001). Heterozygous null Tbx5 mice have
conduction system abnormalities revealed on electrocardiogram (ECG) as PR and PQ interval delays as well as
first- and also second-degree atrioventricular heart block
(AVB). The precise nature of this defect within the conduction system of Tbx5 heterozygous mice is currently
under investigation and will lead to a more complete picture of how Tbx5 may be involved in the patterning of
these specialized cardiac tissues.
HOMEODOMAIN TRANSCRIPTION FACTORS
These transcription factors are characterized by a single
homeodomain DNA binding motif and so far two members
of this class have been identified in the cardiac conduction
system: Msx-2 and Nkx2-5. Three Msx genes closely related to Drosophila msh have been identified in mammalian tissues: Msx-1, Msx-2, and Msx-3 (Davidson, 1995).
Within murine cardiac tissues, Msx-2 has been shown to
be downstream target of Pax-3/splotch (Kwang et al.,
2002), a key player within early cardiac neural crest development (Conway et al., 2000; Epstein et al., 2000);
Pax3 directly represses Msx-2. No cardiac defects were
observed in Msx-2 knockout mice, suggesting that some
redundancy may be present across murine Msx genes
(Satokata et al., 2000). In the chick, Msx-2 mRNA expression is found with the developing conduction system as
early as HH stage 15⫹, where it is found in the lesser
curvature of the tubular heart (Chan-Thomas et al., 1993).
Expression of Msx-2 continues at HH stage 27 within the
developing AV junction, AV rings, and at the crest of the
interventricular septum, regions where the specialized
conduction system is thought to develop (Wessels et al.,
1992). By HH stage 29 and 34, Msx-2 labels the developing
His bundle and bundle branches within the interventricular septum while expression is noticeably absent from
the developing peripheral Purkinje fiber network (Thomas
et al., 2001). These data suggest that Msx-2 may delineate
a population of cardiomyocytes destined to be recruited to
and form the central conduction system elements such as
the AV node and proximal His bundle.
A second and arguably more important member of this
transcription factor subclass is the NK2 class homeodomain transcription factor, Nkx2-5, alternately named Csx
or Tinman (Evans, 1999). In vertebrate embryos, Nkx2-5
is localized within cells that include the cardiogenic mesoderm and as such it is accepted as one of the earliest
markers of heart-forming potential. Functional studies
have shown that postgastrulation expression of Nkx2-5 is
required for the continued maintenance or specification of
cardiomyogenic cell fate. Absence of Nkx2-5 expression
Higher-magnification sample images are shown of sections from another
pair of mice hearts similarly immunolabeled for Cx40. These images
formed the basis of a quantitation carried out using NIH image. Counts
of cells were made within Cx40-positive domains using WGA to label cell
membranes and a DNA intercalating dye to label nuclei. A greater than
50% reduction in the average number of Purkinje fiber cells was found in
Nkx2-5 ⫹/⫺ ventricles compared to wild-type littermates (P ⬍ 0.05). RV,
right ventricle. Scale bars ⫽ 100 ␮m (A, B), 50 ␮m (C, D).
1043
TRANSCRIPTIONAL REGULATION
leads to abnormal heart formation in Drosophila, Xenopus, and mouse (Grow and Krieg, 1998). Homozygous null
Nkx2-5 mice are not viable and do not survive past
10 d.p.c. in utero (Lyons et al., 1995). The majority die
shortly after looping morphogenesis and the hearts of
these animals display altered gene expression patterns.
Our previous work and that of others has shown that
Nkx2-5 is expressed at elevated levels in the forming
AVCS of higher vertebrates, such as chick, mouse, and
even humans (Fig. 1) (Takebayashi-Suzuki et al., 2001;
Thomas et al., 2001). Indeed, the discovery of Nkx2-5
heterozygous mutations in populations of humans that
result in functional and structural cardiac abnormalities
including AV block provides yet further evidence of the
key role that this transcription factor may play in the
development of specialized cardiac tissues (Fig. 2) (Schott
et al., 1998; Benson et al., 1999; Goldmuntz et al., 2001;
Gutierrez-Roelens et al., 2002; Ikeda et al., 2002; Watanabe et al., 2002; McElhinney et al., 2003). Of the 25
NKX2-5 mutations currently identified in humans, the
presence of AV block has been noted to be particularly
associated with those mutations present within the DNA
binding homeodomain (Benson et al., 1999; GutierrezRoelens et al., 2002). Interestingly, the AV block phenotype emerges over the period of postnatal maturation and
it has been suggested that this time course results from
progressive disease of the cardiac conduction system. Similar cardiac abnormalities have been noted in transgenic
mouse models of known human Nkx2-5 mutations (Biben
et al., 2000; Kasahara et al., 2001; Wakimoto et al., 2002).
In one study, conduction defects were more pronounced
when mutant Nkx2-5 protein was expressed during fetal
and neonatal life in contrast to later postnatal time periods (Wakimoto et al., 2002).
Subsequent work has shown that the spatiotemporal
pattern of expression of Nkx2-5 in the developing AVCS
demonstrates a striking correlation with the timing and
location of recruitment of cells to this network of specialized tissues (Thomas et al., 2001). In particular, a wave of
upregulated Nkx2-5 expression coincides with the most
active phase of cellular conscription to the central AVCS,
including the His bundle and its proximal branches. Our
most recent data indicate that recruitment to the peripheral AVCS is also associated with a transient rise and fall
in relative levels of Nkx2-5. Moreover, disruption of this
wave-like pattern by constitutive expression of Nkx2-5
leads to differential effects on genes expressed early and
late during the developmental emergence of a terminally
differentiated Purkinje fiber cell (Fig. 3).
These data in chick would be consistent with our recent
study in mouse, where we found that Nkx2-5 haploinsufficiency caused a dramatic reduction in Purkinje fiber
numbers (Jay et al., 2004). We hypothesized that in these
animals, there was a failure to delineate a large enough
population of cells that could be recruited to the developing conduction system (Fig. 4). The key theme linking
these data is that Nkx2-5 underexpression due to heterozygous mutation or overexpression may perturb differentiation of specialized conduction cells. Thus, precise regulation of Nkx2-5 expression levels through a critical time
period, encompassing late embryonic and early postnatal
development, has the potential to cause conduction system disease in the mature animal.
CONCLUSIONS
Multiple transcription factors from different families
contribute to the formation of the cardiac conduction system. While no single transcription factor describes this
complex specialized network of cells in its entirety, we
now have molecular markers of all subcompartments. The
overlapping expression patterns of these genes and commonalities of both transgenic and disease phenotypes suggest that these factors participate cooperatively to define
specialized tissues. Indeed, several members of the transcription factors described above are known to act synergistically, serving to add an extra level of complexity to
our understanding of the molecular control of cardiac conduction system development.
ACKNOWLEDGMENTS
The authors thank Dr. David Sedmera, Dr. Tom Trusk,
and Mr. T. Gallien for their insight and assistance. Supported by grants HL56728 (to R.G.G.), HL36059 (to
R.G.G.), and HD39946 (to R.G.G., T.X.O.) from the National Institutes of Health and by Merit and Reap awards
(to T.X.O.) from the Research Service of the Department of
Veteran Affairs.
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