Published online before print June 21, 2001, doi: 10.1161/hh1301.092497
© 2001 American Heart Association, Inc.
Molecular Medicine |
Cardiovascular Defects Associated With Abnormalities in Midline Development in the Loop-tail Mouse Mutant
From the Neural Development Unit (D.J.H., N.D.E.G., D.G., J.N.M., A.J.C.), Institute of Child Health, University College London, London UK; the Institute of Molecular Medicine and Genetics (S.J.C.), Medical College of Georgia, Augusta; and the Cardiology Unit (R.H.A.), Great Ormond Street Hospital for Children, London, UK.
Correspondence to Dr Deborah J. Henderson, Neural Development Unit, Institute of Child Health, University College London, 30 Guilford St, London WC1N 1EH UK. E-mail dhender{at}ich.ucl.ac.uk
Abstract
Abstract—Loop-tail (Lp) is a naturally occurring mouse mutant that develops severe neural tube defects. In this study, we describe complex cardiovascular defects in Lp homozygotes, which include double-outlet right ventricle, with obligatory perimembranous ventricular septal defects, and double-sided aortic arch, with associated abnormalities in the aortic arch arteries. Outflow tract and aortic arch defects are often related to abnormalities in the cardiac neural crest, but using molecular and anatomic markers, we show that neural crest migration is normal in Lp/Lp embryos. On the other hand, the heart fails to loop normally in Lp/Lp embryos, in association with incomplete axial rotation and reduced cervical flexion. As a consequence, the ventricular loop is shifted posteromedially relative to its position in wild-type embryos. This suggests that the observed cardiac alignment defects in the Lp mutant may be secondary to failure of neural tube closure and incomplete axial rotation. Double-sided aortic arch is a rare finding among mouse models. In humans, it is usually an isolated malformation, only rarely occurring in combination with other cardiac defects. We suggest that the double-sided arch arises as a primary defect in the Lp mutant, unrelated to the alignment defects, perhaps reflecting a role for the (as-yet-unknown) Lp gene in maintenance/regression of the aortic arch system.
Key Words: congenital heart defects • mouse mutants • double-outlet right ventricle • double-sided aortic arch • midline defects
Cardiovascular defects are the most common cause of congenital disease in humans, occurring in almost 1% of newborns.1 Septation and alignment defects make up the largest single group of cardiac malformations, including ventricular and atrial septal defects, tetralogy of Fallot, and double-outlet right ventricle. The developmental origin of these defects involves disruption of early embryonic events, including cardiac looping and neural crest cell migration. During cardiac looping, the primordial midline heart tube is remodeled into an asymmetric structure that brings the left and right ventricular chambers into alignment with the outflow vessels and atria. To achieve concordance of the ventriculoarterial connections, however, the cardiac neural crest is required, which is involved in septation of the outflow tract to yield separate aortic and pulmonary channels. The aorta is then remodeled so that the initially symmetrical aortic arch becomes left-sided, as the right side regresses.
In view of the importance of midline events in early cardiac morphogenesis (looping, immigration of neural crest cells, and remodeling of the original symmetrical structure), it is not surprising that an association is evident between midline defects of noncardiac structures and cardiac defects of septation and alignment. Midline defects and cardiovascular abnormalities coexist in humans with Opitz syndrome and Jarcho-Levin syndrome.2 3 Although these rare associations are indicative of a developmental link between midline development and cardiac defects, they are not accessible for experimental analysis. An alternative approach is to use the many mouse genetic mutants that exhibit early abnormalities of axial development. Loop-tail (Lp) is a naturally occurring mouse mutant4 that provides a model for the human neural tube defect craniorhachischisis. Lp/Lp embryos fail to initiate closure of the neural tube in the cervical region (so-called closure 1), whereas the forebrain neural tube appears to close relatively normally.5 This results in a severe abnormality in which the neural tube is open from the midbrain to the base of the spine. Lp/Lp embryos also have somite defects and abnormalities in axial rotation.6 A small percentage of cases exhibit gastroschisis, in which the ventral body wall fails to close correctly, resulting in herniation of the abdominal contents.7 Hence, Lp homozygotes exhibit a series of midline developmental defects. For this reason, we decided to examine the development of the cardiovascular system in the Lp mouse. We describe complex cardiovascular defects in Lp/Lp embryos, supporting the idea that abnormalities in the development of the embryonic midline and cardiac alignment defects might be causally related.
Materials and Methods
Mouse Strains and Embryos
The LPT/Le inbred strain, which carries the
Lp mutation, was obtained from
Jackson Laboratories (Bar Harbor, Maine) and has
now been bred to F117. Mice were bred and genotyped as
described
previously5 8 to
generate litters containing
Lp/Lp,
Lp/+, and
+/+ embryos. Embryos were
dissected from the uterus and processed for
histological staining and immunocytochemistry as
described
previously.6 9 The
-smooth muscle actin antibody was obtained from
Sigma Chemical Co (clone
1A4).
Analysis of Embryonic
Vasculature
Embryos were explanted from the uterus into fresh
DMEM containing 10% FCS. The yolk sac and amnion were opened, and the
umbilical cord was left attached. India ink was injected either into
the umbilical artery or the left ventricle. The heart was allowed to
continue beating until carbon particles in the ink had been distributed
throughout the heart and vasculature. Embryos were then fixed by
immersion in cold 4% paraformaldehyde, cleared in a
2:1 mixture of benzyl alcohol and benzyl benzoate, and then either
dissected further and photographed or embedded in paraffin wax for
serial sectioning.
Whole-Mount In Situ Hybridization
The preparation of probes for
cadherin 6 and
RhoB have been described
previously.10 11
The erbB3 probe was a gift from
Dr C. Birchmeier (Max-Delbruck-Center for Molecular Medicine,
Berlin, Germany). Pitx2c and
lefty-2 were obtained from Prof
N. Brown (St. Georges Hospital Medical School, London, UK). The
methodology for the whole-mount in situ hybridization of
Wilkinson12 was followed,
with minor modifications as described
previously.11
Results
Lp
Mutants Develop Double-Outlet Right Ventricle
Histological examination at embryonic
day (E)13.5 revealed a spectrum of cardiovascular
defects in Lp/Lp fetuses,
whereas Lp/+ and
+/+ fetuses had no apparent
defects of the cardiovascular system
(Table
).
The most commonly observed defect was double-outlet right ventricle,
which occurred in all Lp/Lp
fetuses examined
(Figures 1d through 1f). In wild-type fetuses, the
ventriculoarterial connections are concordant
(Figures 1a and 1c), with the aorta arising from the left
ventricle and the pulmonary trunk retaining its original
connection with the right ventricle (arrows in
Figures 1a and 1c). In contrast, in all
Lp/Lp fetuses examined, both
arterial trunks retain their origin from the right
ventricle
(Figures 1d through 1f). Furthermore, in the normal embryo,
the aortic valve, developing in the left ventricle, comes into fibrous
continuity with the mitral valve, whereas the pulmonary valve
is supported at a more cranial level by a free-standing infundibular
sleeve. The arterial trunks then spiral around one another
as they ascend into the mediastinum. In contrast, the
arterial valves in both the aorta and pulmonary
trunk appear at the same level in
Lp/Lp fetuses (arrowheads in
Figure 1e), being separate in most fetuses (n=15) but
appearing as a common valve (arrowheads in
Figure 1h; compare with
Figure 1g), which guards the entrance to a common
arterial trunk exclusively supported by the infundibular
musculature of the right ventricle, in the remainder of the fetuses
(n=3). A ventricular septal defect is an obligatory part of
the pattern of circulation in the
Lp/Lp embryos, in which both
arterial trunks, or a common trunk, arise from the right
ventricle, being necessary to permit the exit of blood from the left
ventricle (compare
Figures 1i and 1j).
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|
Double-Sided Aortic Arch and Associated Aortic
Arch Abnormalities in Lp/Lp
Fetuses
In addition to the abnormalities of
ventriculoarterial connections in
Lp, we also noted major
abnormalities in the arrangement of the aortic arches. Four of six
Lp/Lp fetuses showed
persistence of the right arch at E13.5, in addition to the normal
left-sided arch, resulting in a double-sided aortic arch
(Table
and
Figure 2b). This formed a vascular ring with the arches of
the aorta enclosing completely the trachea and esophagus (arrows in
Figure 2c). In the remaining (2 of 6)
Lp/Lp fetuses, the right side
of the aortic arch had persisted abnormally, but the left side had
partially regressed, resulting in a right-sided aortic arch with a
retroesophageal left subclavian artery (arrow in
Figure 2d). In contrast,
Lp/+ and
+/+ always exhibited regression
of the right side of the aortic arch and maintenance of the
left arch
(Figure 2a). Sectioning of three
Lp/Lp fetuses at E18.5
confirmed the persistence of the double-sided aortic arch throughout
gestation (data not shown).
|
Ink injections into the umbilical artery or directly into
the left ventricle were carried out to examine further the development
of the aortic arch and its associated arteries in the
Lp mutant (n=33). This revealed
narrowing or, in severe cases, interruption of the left aortic arch in
40% (13 of 33) Lp/Lp
fetuses (compare
Figures 2f and 2e).
Cardiac Neural Crest Cell Migration Is Normal
in Lp Mutants
Cardiac neural crest anomalies have been described
previously in other mouse mutants, and in humans, in association with
outflow tract and aortic arch
abnormalities.13 14 15
Lp/Lp embryos were collected at
E10.5 of gestation, when neural crest cells are migrating toward the
cardiac outflow tract, and subjected to whole-mount in situ
hybridization using digoxigenin-labeled riboprobes for the neural crest
markers RhoB,
cadherin 6, and
erbB3. Robust staining of each
neural crest marker could be seen in the region where the cardiac
neural crest cells migrate toward and through the third, fourth, and
sixth branchial arches, in both the wild-type and
Lp/Lp embryos (arrows in
Figures 3a and 3b and data not shown). The cranial and dorsal
root ganglia were also normally sized and positioned in
Lp/Lp compared with their
wild-type littermates
(Figures 3a and 3b). Sectioning of these embryos at the level
of the heart supported this finding, showing that the developing
cranial and dorsal root ganglia were appropriately sized and positioned
despite the widely splayed open neural tube
(Figures 3c and 3d). These data suggest that there are no
marked abnormalities in neural crest cell migration in
Lp/Lp embryos. Because of the
abnormalities in development of the ventricular outlet of
the heart, it was important to determine whether there might be a
specific abnormality in the cardiac neural crest cells migrating into
the developing outflow tract. Most gene expression markers for
migrating neural crest cells are switched off as the cells enter the
environment of the cardiac outflow tract. Therefore, the expression of
-smooth muscle actin, a marker for neural crest cells within the
outflow tract,16 was
examined in the outflow tract cushions of wild-type and
Lp/Lp embryos at E11.5 and was
found to be equivalent between the two genotypes
(Figures 3e and 3f), strongly suggesting that neural crest
cell population of the outflow tract is normal in
Lp/Lp embryos. Finally,
formation of the dorsal root ganglia is dependent on neural crest
migration, and at the level of the cardiac outflow tract, the dorsal
root ganglia appeared to be normally sized in
Lp/Lp fetuses at E13.5 compared
with their wild-type littermates
(Figures 3g and 3h). The thymic rudiments, which are thought
to be specifically of cardiac neural crest
origin,17 18 also
appeared to be normally sized and positioned
(Figures 3i and 3j). These data suggest that there is no
abnormality in neural crest cell migration or differentiation in
Lp/Lp
fetuses.
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Abnormal Heart Looping Associated With Axial
Rotation Defects in Lp/Lp
Embryos
An alternative explanation for the
cardiovascular abnormalities in
Lp is a disturbance of
heart looping, inasmuch as this has been associated with double-outlet
right
ventricle.19 20 21
Examination of embryos at E8.5, as the heart is just beginning to loop,
revealed that although looping always occurs to the right in
Lp/Lp embryos, as in wild-type
littermates, there are marked abnormalities in the looping process. In
wild-type embryos, the base of the ventricular loop lies
90o to the midline, but in
Lp/Lp embryos, it is rotated
clockwise and displaced to the right (see dotted lines in
Figure 4a). This is still visible at E9.5 and E10.5
(Figures 4b through 4e).
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Although the heart appears to be displaced in relation to
the orientation of the embryonic head in
Lp/Lp embryos at E9.5 and
E10.5, it remains in the same orientation as the forelimb buds
(Figures 4d and 4e), by virtue of the incomplete axial
rotation that characterizes
Lp/Lp
embryos.7 Hence, the head and
the trunk are misaligned in
Lp/Lp embryos, which might
result in misalignment of the outflow vessels with respect to the
ventricular chambers, leading to the development of
double-outlet right ventricle.
Lp/Lp embryos also
exhibit abnormalities in cervical flexure. At E8.5, compared with their
wild-type littermates, Lp/Lp
embryos have reduced cervical flexure
(Figure 4a). This continues to be marked throughout
development; at each stage, considerably more of the first and second
branchial arches are visible in a frontal view of
Lp/Lp embryos than of
Lp/+ and
+/+ littermates (large arrow in
Figures 4a and 5b). Side views at E9.5 and E13.5 confirm that
cervical flexure is reduced in
Lp/Lp embryos compared with
their wild-type littermates
(Figures 5a and 5c).
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Apparently Normal Left-Right Axis Formation in
Lp/Lp Embryos
As a consequence of the failure in regression of
the right side of the aortic arch system, we looked for evidence of
laterality defects in Lp/Lp
embryos. All Lp/Lp embryos
(n=25) turned to the right side, as in the wild-type embryos, and the
heart looped to the right
(Table).
Moreover, in every case examined (n=18), the lungs were normal, with
four lobes on the right and one on the left, and there were both
morphologically left and right atrial appendages
(Figures 6a and 6b), suggesting that pulmonary and/or
atrial appendage isomerism was not a feature of
Lp/Lp fetuses. Finally, we
examined the expression of the genes
Pitx2c and
lefty-2 at E8.5, the stage at
which the left-right axis is being specified.
Pitx2c was expressed
symmetrically in the forebrain of
+/+,
Lp/+, and
Lp/Lp embryos, whereas in the
heart, Pitx2c exhibited
markedly asymmetric expression. The left sinus horn, which becomes
incorporated into the left ventricular groove as the
coronary sinus, was strongly positive for
Pitx2c transcripts in all the
genotypes
(Figures 6c and 6d). Examination of
lefty-2 expression at E8.5
revealed asymmetric localization of transcripts in the left lateral
plate mesoderm (data not shown), with no discernible differences in
expression pattern between +/+,
Lp/+, and
Lp/Lp embryos. These findings
effectively rule out laterality defects as a cause of the malformations
seen in the Lp
mutant.
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Discussion
Cardiovascular defects have not previously been reported in the Lp mouse mutant, which has been studied mainly as a model of severe neural tube closure defects. We describe a range of complex cardiovascular defects in Lp homozygotes, including a defect of cardiac alignment, double-outlet right ventricle, and structural abnormalities of the aorta, including double-sided aortic arch.
Looping Disturbances as a Cause of
Cardiac Alignment Defects
Double-outlet right ventricle, accompanied by an
obligatory perimembranous ventricular septal defect, was
found in all the Lp/Lp fetuses
examined. This defect has been associated with both deficiencies in the
cardiac neural crest and with abnormalities in cardiac
looping.14 20 22 23
We do not favor a neural crest abnormality as a cause of double-outlet
right ventricle in the Lp
mutant, because we observed robust cardiac neural crest migration, as
shown by the expression of several well-characterized neural crest
markers. In addition, comparable numbers of -smooth muscle
actin–positive neural crest cells were seen in the outflow tract
cushions of all the genotypes. Normal development of other
neural crest–derived structures, including the cranial ganglia, dorsal
root ganglia and thymus, was also observed. These data suggest that
defective neural crest cell colonization of the outflow tract is not
responsible for the cardiac alignment defects seen in
Lp. Instead, we suggest an
abnormality in heart looping as the likely cause of the cardiac
alignment defects seen in Lp/Lp
fetuses.
If the processes of heart looping and remodeling are compromised, the apposition of the great vessels and ventricles can be disturbed, resulting in alignment defects, such as double-outlet right ventricle and ventricular septal defects. In the chick embryo, treatment with retinoic acid at stage 15 of development appears to induce cardiac looping abnormalities, leading to a spectrum of double-outlet right ventricle and ventricular septal defects.20 24 The cardiac alignment defects described in these embryos closely resemble the abnormalities that we observe in Lp/Lp fetuses.
Cardiac Looping Abnormalities Are Likely to Be
Secondary to Failure of Neural Tube Closure and/or Axial Turning
Defects in Lp
In addition to cardiovascular defects,
Lp homozygous embryos have a
variety of other defects, including an open neural tube from the
midbrain to the base of the spine, and reduction in cervical flexure,
presumably as a result of alteration in mechanical forces within the
open neural tube. In the chick embryo, experimental prevention of
cervical flexure results in a spectrum of cardiac looping
disturbances.25
Moreover, prevention of cervical flexure can result in double-outlet
right ventricle unrelated to defects in neural crest cell
migration.21 Therefore, it
is possible that the looping disturbances and alignment defects
in Lp result from a reduction
in cervical flexure, which can be observed as early as E8.5, before the
heart has completed looping morphogenesis.
In addition to the defects in neural tube closure, Lp mutants also exhibit axial rotation defects, which result in incomplete embryonic turning. These types of defects have been associated with cardiac looping abnormalities in a number of mouse mutants, including those for the BMP2, no turning, and SIL genes,26 27 28 suggesting a close association between these two developmental processes.
Abnormal Regression/Retention of the Aortic
Arch in Lp
The range of aortic arch malformations manifested by
Lp/Lp fetuses can be explained
on the basis of variable regression of a persistent double-sided
aortic arch. The aortic arch system initially develops in a symmetrical
fashion, but by E12.5 in the normal mouse embryo, the right side of the
aortic arch is regressing, leaving a predominantly left-sided arch.
Concomitantly, remodeling results in an asymmetrical pattern of aortic
arch derivatives.29 The
mechanism behind retention and/or regression of arch elements is poorly
understood. In humans, complete double-sided arch is rare and usually
occurs in isolation.30
Variations of this, such as right-sided aortic arch with aberrant
origin of the subclavian artery, are much more common and are
frequently found alongside other lesions, such as common
arterial trunk and tetralogy of
Fallot.30 Right-sided and
interrupted arch were both common findings in
Lp/Lp fetuses, probably
reflecting partial regression of a persistent double arch. Because the
aortic arch phenotype in
Lp is highly variable, it
may be that the origin of the arch structures differs between embryos.
For example, in some cases, the left fourth aortic arch artery may form
the definitive left arch (as in the normal situation), whereas in other
cases, the left third aortic arch artery might form the definitive
arch. The abnormal right side of the double arch is formed from the
arterial duct (ductus arteriosus) and a retroesophageal
subclavian artery. The precise origin of these vessels will be the
subject of future studies.
The double-sided arch abnormality observed in
Lp does not appear to have been
previously reported in any mouse mutant. Double-sided aortic arches are
found in 5% of rat embryos treated with the chemotherapeutic drug
doxorubicin, whereas almost 25% develop a right-sided aortic arch,
supporting the idea that these two abnormalities are manifestations of
the same defect.31 It is
possible that aortic arch defects might have gone unnoticed in existing
mouse mutants or might be associated with other, lethal anomalies that
lead to death before E13.5, when abnormalities in regression/retention
of the arch system become obvious. It is also possible that defects of
aortic arch retention/regression are relatively specific for the
Lp gene. The absence of mirror
imagery or pulmonary and atrial appendage isomerism in
Lp/Lp embryos and the normal
expression of genes such as
Pitx2c and
lefty 2 suggest that the
Lp gene is unlikely to be
involved in setting up the definitive left-right axis. However,
Lp might act downstream from
the genes that specify left-right symmetry; thus, the double-sided
aortic arch seen in Lp/Lp
fetuses may reflect minor abnormalities in left-right axis
formation.
Acknowledgments
This research was funded by the British Heart Foundation (Drs Henderson and Anderson), the Wellcome Trust (Drs Copp, Greene, and Gerrelli), the Medical Research Council (Dr Murdoch), a Basil O’Connor Starter Scholar Research Award (No. FY97-0690) from the March of Dimes Birth Defects Foundation, National Institutes of Health Grants HL-60104 and HL-60714, and an Outside Consortium on PO1 HL-52813 grant (Dr Conway). We would like to thank Dr Margaret Kirby for first recognizing anatomic abnormalities within the arch arteries in Lp/Lp fetuses.
Footnotes
Original received December 21, 2000; revision received April 6, 2001; accepted May 2, 2001.
1 These authors contributed equally to this study. 
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 J. N. Murdoch, K. Doudney, C. Paternotte, A. J. Copp, and P. Stanier Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification Hum. Mol. Genet., October 1, 2001; 10(22): 2593 - 2601. [Abstract] [Full Text] [PDF]
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