© 1998 American Heart Association, Inc.
Original Contributions |
Sox4-Deficiency Syndrome in Mice Is an Animal Model for Common Trunk
From the Department of Anatomy and Embryology (J.Y., P.A.J.d.B., A.F.M.M., W.H.L.), Academic Medical Center, University of Amsterdam, and the Department of Immunology (M.W.S., H.C.), University of Utrecht, The Netherlands.
Correspondence to Wouter H. Lamers, Department of Anatomy and Embryology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands. E-mail w.h.lamers{at}amc.uva.nl
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Abstract—Embryonic mice lacking functional Sox4 transcription factor die from cardiac failure at embryonic day (ED) 14. Heart morphogenesis in these embryos was analyzed in hematoxylin-azophlochsin or immunohistochemically stained, 3-dimensionally reconstructed serial sections between ED12 and ED14. Although Sox4 is expressed in the endocardially derived tissue of both the outflow tract and atrioventricular canal, Sox4-deficient hearts only suffer from defective transformation of the endocardial ridges into semilunar valves and from lack of fusion of these ridges, usually resulting in common trunk, although the least affected hearts should be classified as having a large infundibular septal defect. The more serious cases are, in addition, characterized by an abnormal number and position of the semilunar valve-leaflet anlagen, a configuration of the ridges typical for transposition of the great arteries (with linear rather than spiral course of both ridges and posterior position of the pulmonary trunk at the level of the valve), and variable size of the aorta relative to the pulmonary trunk. The coronary arteries always originated from the aorta, irrespective of its position relative to the pulmonary trunk. The restriction of the malformations to the arterial pole implies that the interaction between the endocardially derived tissue of the outflow tract and the neural crest–derived myofibroblasts determines proper development of the arterial pole.
Key Words: mouse • semilunar valve • transposition • common trunk • outflow tract
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Introduction |
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Congenital malformations of the heart are the most common birth defects in man, accounting for 0.5% to 1% of live births, 10% of stillbirths, and possibly up to 20% of spontaneous abortions.1 2 3 Thus far, the systematic analysis of these defects has rested almost entirely on findings in human neonates with these structural anomalies. As a consequence, little direct information is available about the etiology and pathogenesis of the malformations. In particular, it is usually not known to what extent a particular malformation can be traced to a single morphogenetic event or process. However, recent progress in molecular and developmental biology has changed the general approach for the study of cardiovascular diseases profoundly. In particular, the technique to genetically modify the expression of genes in vivo has proven to be a powerful approach to identify genes that are involved in the development of specific cardiac malformations. A case in point is the Sox4-null mutant.4 The Sox4 gene is a member of the Sox (for Sry-box) family of transcription factors, of which more than a dozen members have been identified in the mouse.5 6 The Sox4 protein, which binds to the sequence motif AACAAAG,7 has been shown to be a transcriptional activator in immature B- and T-lymphocytes in adult mice.7 However, gene disruption in mice resulted in cardiac failure because of the defective development of the semilunar valves.4 Homozygous Sox4-deficient embryos could not be distinguished externally from their littermates until the onset of valvular morphogenesis in the arterial pole of the heart (ED12 to ED13). Then, they rapidly developed generalized edema to die at ED14. Dying mutant embryos typically displayed an oscillatory, nearly futile movement of blood in the arterial pole of the heart, showing that the valvular function of the outflow tract was affected. A preliminary histological examination revealed that the embryos suffered from common arterial trunk and defective semilunar valve development.4 We now show that Sox4 deficiency causes a syndrome with, in addition to impaired semilunar valve development, malformations ranging from infundibular septum defect to complete transposition of the great arteries.
Common trunk is a still poorly understood malformation of the ventriculo-arterial junction. Due to the lack of an established concept of ventriculo-arterial development and malformations, some opt for purely descriptive definitions and use the term "common trunk" to mean "single arterial trunk that leaves the heart by way of a single arterial valve and gives rise directly to the coronary, systemic, and one or both pulmonary arteries."8 9 Others take a more ontogenetic view and define common trunk as the most severe form of a "trunco-conal septal defect,"10 whereas others have been intrigued by its similarity with tetralogy of Fallot and claim that pulmonary atresia plus partial or complete absence of the aorticopulmonary septum are its landmark features.11 12 Irrespective of all these uncertainties, common trunk in genetically defined mouse models becomes manifest after ED12,4 13 14 that is, at the onset of the period in which the structural transformation of the embryonic outflow tract into the ventriculo-arterial junction occurs. The outflow tract of the preseptation embryonic heart is a long, slowly conducting myocardial structure that functions as a sphincter at the arterial pole of the heart prior to the emergence of the 1-way semilunar valves.15 16 Extensive remodeling of the tissues of the outflow tract, as well as immigrating cells of the neural crest are responsible for connecting the right ventricle with the pulmonary trunk and the left ventricle with the aorta, that is, for the developmental formation of the definitive ventriculo-arterial junction. The precise mechanisms underlying this important architectural adaptation are still debated.17 18 19 20 21 22 23 Based on our findings in the Sox4-deficient mouse model and reports in the literature, we will argue that the tissue interactions between the endocardially derived cells of the outflow tract and cells derived from the neural crest determine the developmental fate of the embryonic outflow tract.
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Materials and Methods |
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Animals
Details concerning the method used to disrupt the Sox4 gene have been described elsewhere.4 Homozygous Sox4-disrupted embryos were identified by Southern blot analysis and accounted for 18% to 20% of the litter at embryonic day (ED) 12, 13, and 14 (not shown). Embryos were fixed either in a mixture of ice-cold methanol: acetone:water (2:2:1) or in 4% formaldehyde diluted in PBS (150 mmol/L NaCl; 10 mmol/L Na-phosphate; pH 7.4). After overnight fixation, the embryos were dehydrated in a graded series of ethanol, embedded in Paraplast plus, serially sectioned (7 µm thick), and mounted on poly-L-lysine– or 3-aminopropyltriethoxysilane–coated slides for immunohistochemistry or in situ hybridization staining, respectively. The sections were stored at 4°C until use.
Immunohistochemistry
The detailed procedure for the histological
processing of the tissues has been described.24
Briefly, the serial sections were incubated overnight with alternately
monoclonal antibodies against 
-myosin heavy chain (-MHC;
1:1025 ), ß-myosin heavy chain (ß–MHC;
1:1026 ), -smooth-muscle actin (-SMA;
1:1000; Sigma IMMH-2), desmin (1:50; Monosan, Mon 3001, clone 33), and
a polyclonal antibody against fibronectin (1:6000; AB 1942, Brunschwig
Chemie). After incubation with the primary antibodies, the sections
incubated with monoclonal antibodies were stained with rabbit
anti-mouse IgG (1:7500; noncommercial) followed by incubation with goat
anti-rabbit IgG (1:250; noncommercial), whereas the sections incubated
with the polyclonal antifibronectin antiserum were stained directly
with goat anti-rabbit IgG. Antibody binding was demonstrated with
rabbit peroxidase-antiperoxidase complex (1:750; Nordic,
Tilburg, The Netherlands) and
3,3-diaminobenzidine-tetrahydrochloride and
H2O2 as
substrates.
In Situ Hybridization
In situ hybridization was performed on formaldehyde-fixed
sections to visualize the expression of Sox4, Nfatc, and SERCA 2
(sarcoendoplasmic reticulum calcium ATPase 2) as described in detail
previously.27 The cRNA probes were transcribed
from linearized cDNA in pBluescript using T3 RNA polymerase and
35S-UTP. The Sox4 probe (EcoRI-Sacl fragment; 300
bp4) contained unique, untranslated sequences
from the 5' end of the mRNA. The Nfatc3 probe (SacII-XhoI
fragment28 ) was provided kindly by Dr G.R.
Crabtree (Stanford, Calif). Selected hearts of Sox4-mutant mice
were reconstructed 3-dimensionally as described29
and rendered with the help of a medical artist.
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Results |
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Development of the Arterial Pole in Wild-Type and Heterozygous Littermates of Sox4-Deficient Mice
No differences in morphological development were observed between wild-type and heterozygous littermates of Sox4-deficient mice (Figure 1A
through 1D). In ED12 mice, the aorta
and pulmonary trunk have become separate vessels at and above
the distal rim of the myocardium of the outflow tract. The
fusion of the ridges continues toward the ventricle during ED13. Before
fusion, the distal ends of the parietal and septal endocardial ridges
each contain a central rod of condensed, -SMA–positive mesenchymal
cells of neural crest origin. When both ridges fuse, their central rods
of condensed mesenchyme do so, too, by forming a central mass of
-SMA–positive cells. At ED14, the -SMA–positive mesenchyme is
still recognizable at the level of the valves. Further upstream,
however, the presence of many apoptotic cells reveals that,
soon after fusion, it is being eliminated and replaced by myocardial
cells that can be seen to migrate into the outlet septum; that is, the
septum forms between the subaortic and subpulmonary outlets on
fusion of the septal and parietal endocardial ridges. The scallops of
the semilunar valve leaflets in the aorta and pulmonary trunk,
and the coronary arteries become discernible at ED13. The
normal morphogenesis of the arterial pole therefore is
virtually complete at ED14, which is comparable to 7 weeks of
development (Carnegie stage 19 to 20) in man.
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Expression of Sox4 mRNA in Wild-Type and Heterozygous Littermates
of Sox4-Deficient Mice
Sox4 mRNA is expressed abundantly in the nervous system, thymus,
mesenchyme surrounding the branchial arch arteries, trachea, and
esophagus, but not in the tissue of the aorticopulmonary septum
(Figure 1E
, 1F, and 1I through 1L). Sox4 expression levels in the
endocardially derived tissues of the outflow tract and
atrioventricular canal are similar.
Expression of -MHC, ß-MHC, -SMA, Desmin, Fibronectin, and
Nfatc in Heterozygous and Homozygous Sox4-Deficient Embryos
We used - and ß-MHC expression as a parameter to
monitor myocardial development, fibronectin expression to selectively
delineate the endocardially derived tissues, and, finally, -SMA and
desmin expression to follow both the maturation of the
myocardium and the population of the endocardial
tissue–derived cells with neural crest–derived
cells.24 30 We observed no conspicuous
differences in the spatio-temporal pattern of expression of these genes
between deficient embryos and their wild-type or hemizygous
littermates, suggesting that Sox4-deficiency does not primarily affect
myocardial or endocardial development. Because Sox4-deficient mice
resemble Nfatc-deficient mice with respect to the (failing) development
of the semilunar valves, Nfatc expression in the endocardium was
investigated and found to be normal (cf Figure 1G and 1H).
Malformations of the Arterial Pole of the Heart in
Sox4-Deficient Mice
A total of 21 Sox4-deficient embryos were studied
histologically, 4 of which were from ED12, 8 from ED13,
and 9 from ED14. Cardiac morphogenesis was found to become
progressively retarded in these embryos but did not stop. For example,
in only 25% of Sox4-deficient ED13 hearts, coronary arteries
were seen to develop, whereas this was the case in all hearts of
wild-type littermates and in all ED14 Sox4-deficient embryos.
Furthermore, 2 dorsal aortae were still present in 7 of 8 ED13
Sox4-mutant embryos, whereas the right dorsal aorta had disappeared in
all wild-type littermates. In affected ED14 embryos, the right dorsal
aorta, if present, had diminished greatly in diameter.
At ED12, nearly normal amounts of endocardially derived tissue
was found in the outflow tract of Sox4-deficient hearts (Figure 2), suggesting that the
morphogenesis of the endocardial ridges rather than the formation of
endocardially derived tissue is primarily affected. In ED13 and ED14
hearts, the developing septal and parietal endocardial ridges could be
distinguished from the so-called intercalated endocardial
ridges18 by the presence of a rod of condensed,
-SMA–positive mesenchyme (Figures 3 and 4). Except in the most seriously
affected embryos, the 2 endocardial ridges were always present, but
the number and position of intercalated ridges between them differed
considerably. Although we noted no correlation between the number of
intercalated ridges and the severity of the malformation, a normal
position of the intercalated ridges was seen only in the least affected
hearts.
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Sox4-Deficiency Syndrome
In the Table, the embryos are
arranged in order of increasing severity of their malformation at the
arterial pole. Features associated with increasing severity
of the malformation were fusion of the endocardial ridges on the
posterior wall of the outflow tract near the lesser curvature, fusion
of the condensed mesenchymal rods on the posterior wall of the outflow
tract, side-by-side or posterior position of the pulmonary
trunk, difference in size of the pulmonary trunk and aorta,
abnormal number or position of the intercalated ridges, and, finally,
the presence of esophago-tracheal fistula. Based on the position of the
ascending aorta relative to the pulmonary trunk, we
distinguished 4 groups.
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The least severe grade of malformation (Figures 2A through 2C,
5A, and 6;
group 1 of the Table; 
25% of cases) was characterized by a complete
separation of aorta and pulmonary trunk, 2 separate semilunar
valve anlagen, and a remnant of the developing outlet septum below the
valvular rings. Usually, all 6 endocardial swellings could be
identified at the level of the developing valves. Although the
endocardial ridges had fused at and just below the valves, they had
failed to do so further toward the embryonic right ventricle. As a
result, a large infundibular ventricular septal defect
existed in all cases. The aortic arch and arterial duct
were always on the left side. Furthermore, the diameter of the aortic
and pulmonary roots were usually comparable, with the
pulmonary root located anterior to that of the aorta.
In more serious malformations (Figures 5B and 7; group 2 of the Table; 25% of
cases), the ascending aorta and pulmonary trunk were separate
vessels to the extent that the pulmonary arteries arose from
the pulmonary trunk and coronary arteries arose from
the aorta. However, at and below the level of the semilunar valve
anlagen, only a single lumen was present. Furthermore, the root of
the pulmonary trunk and aorta typically occupied side-by-side
positions. Nevertheless, the morphological presentation of
the endocardial ridges was still rather normal with the septal and
parietal ridges each following their characteristic, spiral downstream
course in the outflow tract.
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As the severity of the malformation increased further, posterior
position of the pulmonary trunk relative to the aorta was found
invariably (Figures 3, 4, and 5C; group 3 of the Table; 35% of cases).
At the level of the semilunar valve anlagen, only 3 or 4 endocardial
swellings were found. The swellings containing the condensed
mesenchymal rods typically occupied a posterior, adjacent position,
that is, without intercalated swelling between (Figure 3B, 3C, and 3E).
Further toward the ventricle, the septal and parietal ridges were fused
into a single ridge that was positioned on the posterior wall of the
outflow tract, that is, near the lesser curvature (Figures 3C, 3F, and 4D). In 4 embryos, this fused posterior portion of the ridges
occupied more than one third of the length of the outflow tract so
that, in addition, the pillars of condensed mesenchyme had become
fused. Because the condensed mesenchyme in the endocardial ridges is
continuous with the strongly -SMA–positive mesenchyme of the
aorticopulmonary septum, a ring of -SMA–positive mesenchyme
encircles the pulmonary outlet in this group (Figure 5C). The
relative diameters of pulmonary trunk and aorta varied
substantially, the most severe cases presenting with
stenosis of the pulmonary trunk (Figures 3 and 5C).
Narrowing of the pulmonary trunk always was accompanied by
absence of the arterial duct, whereas the aortic arch was
left-sided and normal in diameter. On the other hand, when the diameter
of the aortic root was smaller than that of the pulmonary trunk
(Figure 4), the embryo also had an enlarged diameter of the
arterial duct. In all these cases, both the aortic arch and
the arterial duct were situated on the left side. The
coronary artery anlagen always were associated with the aorta
(Figure 3A and 3D).
A single arterial trunk, which was a direct continuation of
the outflow tract and from which both the coronary arteries and
the pulmonary arteries originated, was found in 15% of cases
(Figures 2D through 2F, 5D, 5E, and 8;
group 4 of the Table). In the ED14 embryo that is illustrated in Figure 8, the arterial duct was absent, whereas the aortic arch
was on the right side. Tissue with the same staining properties as
those of the endocardial ridges surrounded the lumen of the outflow
tract as a cuff, but rods of condensed mesenchyme were absent. Two ED12
specimens revealed that this condition arose as a result of merging of
the distal portion of the endocardial ridges on the anterior side of
the lumen of the outflow tract (Figure 2D through 2F). As a result, the
aortic sac is not divided between ascending aorta and pulmonary
trunk. The ED12 embryos further resembled the ED14 specimen in that
relatively few -SMA–positive cells were seen in the endocardial
tissue and that the right-sided fourth branchial arch artery was better
developed than the left, whereas both sixth-arch arteries were reduced
in size. Two embryos of this group suffered, in addition, from a
hypoplastic left ventricle.
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Associated Malformations in Sox4-Deficient Mice
Branchial arch anomalies in ED13 and ED14 embryos, such as absence
(4 cases) or increased size (2 cases) of the arterial duct,
were correlated with the size of the pulmonary trunk relative
to that of the aorta. An esophagotracheal fistula was found in 4 of the
more serious cases (Figure 8). These malformations probably
represent an independent feature of Sox4 deficiency, because
the transcription factor also is expressed strongly in the mesenchyme
of the branchial arches and on the dorsal surface of the trachea.
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Discussion |
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Even though only a single gene (Sox4) was inactivated, we observed a range of malformations of the arterial pole of the heart. The anomalies ranged from a solitary defect in the proximal (conal) portion of the outlet septum, that is, with separate valve anlagen supporting the roots of the aorta and pulmonary trunk (type IV according to Angelini and Leachman10 ), via a common origin of aorta and pulmonary trunk at the level of the valve anlagen (type 1 according to Collett and Edwards,31 type A1 according to van Praagh and van Praagh,11 and type II according to Angelini and Leachman10 ), to 2 pulmonary artery orifices in the dorso-caudal truncal wall (type 2 according to Collett and Edwards,31 type A2 according to van Praagh and van Praagh,11 and type I according to Angelini and Leachman10 ). Additionally, we did observe embryos in which the diameter of the pulmonary trunk was much smaller than that of the aorta (van Praagh and van Praagh's type A311 ) and embryos in which the diameter of the aorta was much smaller than that of the pulmonary trunk (van Praagh and van Praagh's type A411 ). Such a wide spectrum in the phenotypic presentation of a single gene deficiency is probably characteristic of genes that are either components of a signal-transduction pathway or transcription factors. Most likely, the downstream members of these signal-transduction pathways or the target genes of the transcription factors continue to be active, but as a consequence of a lack of regulation, the level of these downstream activities is no longer (tightly) controlled, thus allowing the emergence of large interindividual differences in phenotype. Our finding that Nfatc is expressed in Sox4-deficient embryos and vice versa,32 therefore does not prove the presence of independent regulatory pathways. On the other hand, accurate descriptions of single gene–deficiency syndromes are necessary to decide which congenital malformations may share a common deficiency and to obtain a sufficiently large catalogue of syndromes to deduce which regulatory pathways are involved in a particular morphogenetic process.
Both Sox4 and Nfatc32 33 deficiency are
characterized by death due to heart failure on day 14 of embryonic
development. The observed regurgitation of blood in
embryos of this age shows that the lack of transformation of the distal
portion of the endocardial ridges into one-way semilunar valves is, in
all likelihood, the direct cause of the heart failure in both the
mildly and seriously affected embryos (compare with References 3434 to
36). The timing of the onset of this functional failure strongly
supports our hypothesis that it is the remodeling of endocardial tissue
into valvular structures rather than the formation of the
endocardial tissue itself that is primarily affected. Before the
development of the semilunar valves on ED13 and ED14, an adequate
amount of endocardially derived stuffer tissue in the outflow
tract suffices to allow the outflow tract to function as a myocardial
sphincter that prevents regurgitation of
blood.16 Although population of the endocardial
cushions of the atrioventricular canal by neural crest
cells is quantitatively insignificant compared with that of the
endocardial ridges of the outflow tract,21 37
Sox4 expression levels in both endocardial tissue–derived structures
are comparable (Figure 1F, 1J, and 1L). Sox4 expression therefore is
localized almost certainly in endocardially derived cells. Because the
malformations in Sox4-deficient embryos are largely restricted to the
arterial pole, whereas the development of the
atrioventricular cushions is not visibly affected, our
study suggests that it is the interaction between the neural
crest–derived myofibroblasts30 and the
endocardially derived original cells of the outflow tract, that
determines proper development of the arterial pole.
The least affected Sox4-deficient hearts, strictly
speaking,8 9 do not suffer from common trunk but
should be classified as having a large infundibular
ventricular septal defect. In the more serious
cases, the following are seen: a linear rather than a spiral
configuration of the ridges and, consequently, a posterior position of
the pulmonary trunk at the level of the valve (the
configuration present in transposition of the great arteries), an
abnormal number and position of the intercalated ridges relative to the
parietal and septal endocardial ridges, lack of fusion of the ridges,
and variable size of the aorta relative to the pulmonary
trunk. In the most serious cases, even the formation of the endocardial
ridges failed, so that a cuff of endocardial tissue, in which the
neural crest–derived rod(s) of condensed mesenchyme could not even be
identified as such, continued to surround the lumen of the outflow
tract. Because the emergence of spiraling septal and parietal
endocardial ridges coincides temporally with the ingrowth of
-SMA–positive neural crest cells30 and
because the position of these 2 endocardial ridges greatly differs
between individual affected mice, it appears that the migration of the
neural crest cells into the endocardial tissue of the outflow tract is
poorly guided in Sox4-deficient mice. The association of an abnormal
position of the endocardial ridges and an abnormal number and position
of the intercalated ridges with the presence of a single
arterial outlet and often with a difference in diameter of
aorta and pulmonary trunk, implies a correspondingly abnormal
position of the aorticopulmonary septum.
We know of only 2 earlier descriptions of common trunk in
embryos.38 39 For that reason, the morphogenetic
events underlying the development of common trunk are deduced mostly
from observations in human neonates. The conventional explanation of
common trunk is a complete or partial failure of down-growth of the
aorticopulmonary septum, together with incomplete development
of the endocardial ridges of the outflow tract (eg, References 88 to 10,
38, and 40). Some consider the abnormal development of the ridges to be
secondary to faulty development of the aorticopulmonary septum
(eg, Reference 99 ). In support of this view are the extensive population
of the ridges of the outflow tract by neural crest
cells21 37 and the prevalence of malformations of
the arterial pole of the heart in animal models in which
genes that are expressed in neural crest derivatives are
disrupted13 14 41 42 43 44 45 (for a review, see
Reference 4646 ). Accordingly, common trunk, together with tetralogy of
Fallot and interrupted aortic arch, is described often as one of the
symptoms identifying a typical neurocristopathy in human
neonates,47 but it almost never is associated
with a configuration reminiscent of (complete) transposition of the
great arteries. In Sox4-deficient embryos, however, we did not observe
tetralogy of Fallot or interrupted aortic arch, whereas we did observe
the configuration of the endocardial ridges that corresponds with
transposition in 50% of cases. These differences in
presentation are suggestive of distinctive roles for the
endocardially derived cells and the neural crest cells in the
regulation of morphogenesis of the outflow tract. In addition, the lack
of differentiation of the semilunar valves in Sox4- and
Nfatc-deficient mice, and the almost normal development of semilunar
valves in common trunk caused by the dysfunction of neural crest cells
(eg, resulting from deficiency of nuclear retinoic acid
receptors13 44 or the Pax3 transcription
factor14 ) also support a distinct morphogenetic
role for endocardially derived and neural crest–derived tissues.
Conclusion
The Sox4-deficiency syndrome can be ascribed to a defective
function of the endocardial tissue of the outflow tract, leading to a
lack of development and/or fusion of the endocardial ridges, a lack of
development of the semilunar valves, and an arrangement of the
ventriculo-arterial connection corresponding with
transposition of the great arteries. The Sox4-deficiency syndrome is
therefore an animal model for abnormal development of the
ventriculo-arterial junction because of a defective
function of the endocardially derived tissue. The fate of the
endocardial tissue–derived structures involved in the formation of the
ventriculo-arterial junction could be followed, thanks to
the presence of the highly characteristic rods of condensed mesenchyme.
The restriction of the malformations to the arterial pole,
even though the Sox4 gene is equally expressed in the endocardially
derived tissue of the atrioventricular canal, implies
that the interaction between the endocardially derived tissue of the
outflow tract and the neural crest–derived
myofibroblasts30 determines proper development of
the arterial pole. The lack of differentiation of the
semilunar valves in Sox4- and
Nfatc-deficient32 33 mice and their normal
development in animal models with neural crest deficiencies implies
that the neural crest does not regulate the development of the
semilunar valves.
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Received June 1, 1998; accepted August 20, 1998.
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References |
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