© 1997 American Heart Association, Inc.
Articles |
Compartment-Selective Sensitivity of Cardiovascular Morphogenesis to Combinations of Retinoic Acid Receptor Gene Mutations
From the Institute for Genetic Medicine (R.Y.L., H.M.S.), Department of Cell and Neurobiology, University of Southern California School of Medicine, Los Angeles; the Departments of Biochemistry, Medicine, and Oncology (J.L., V.G.), McGill University, and Molecular Oncology Group (J.L., V.G.), Royal Victoria Hospital, Montreal, Quebec, Canada; and the Gene Expression Laboratory (R.M.E., H.M.S.), Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, Calif.
Correspondence to Dr Henry M. Sucov, Institute for Genetic Medicine, Department of Cell and Neurobiology, University of Southern California School of Medicine, 2250 Alcazar St, IGM 240, Los Angeles, CA 90033. E-mail sucov{at}zygote.hsc.usc.edu
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Abstract |
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Abstract Several aspects of normal cardiovascular development require signaling by the vitamin A metabolite retinoic acid. We have previously established germ-line mutations in mice in the genes that encode the RAR
1,
RARß, and RXR retinoic acid receptors as a means of studying the
function of these receptors in vivo. Although mutation of RXR
results in fetal ventricular defects, the RAR1 and
RARß mutations are apparently nonphenotypic in the heart and
elsewhere. In this study, we have established and analyzed
combinations of these receptor gene mutations. Malformations of the
ventricular chamber (chamber hypoplasia and muscular
ventricular septal defects), conotruncus (double-outlet
right ventricle, transposition, and membranous ventricular
septal defects), aortic sac (persistent truncus arteriosus and
aorticopulmonary window), and aortic arch–derived arteries
were recovered in various combinations of the RAR1, RARß, and
RXR gene mutations. Depending on the combination of receptor
mutations, selective defects were obtained in specific
cardiovascular compartments, suggestive of differential
expression or function of each receptor within domains of the
developing heart.
Key Words: gene disruption • retinoid teratology • genetic deficiency • retinoid X receptor
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Introduction |
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The vitamin A derivative RA has a critical role in multiple aspects of cardiovascular morphogenesis and in many other aspects of embryonic development. Historically, the biological role of RA in animals has been inferred from the numerous phenotypes that emerge after experimental perturbation of RA status. A broad spectrum of cardiovascular malformations (described below) are prominent consequences of vitamin A deficiency1 2 and vitamin A or RA excess exposure3 4 5 6 in mammals, with a comparable set of malformations observed in avian embryos as well.7 8
The biological effects of RA are mediated by receptors of the nuclear
receptor family, which function in the nucleus as ligand-dependent
transcription factors.9 There are two subfamilies of RA
receptors, the RARs and the RXRs, each with three members: , ß,
and 
.10 A fairly sophisticated level of understanding
of the molecular biochemistry of RA transcriptional activation has been
uncovered over the last several years and has recently been
reviewed.11 12 13
As a means to better understand the role of RA and the RA receptors, we
and others have initiated a genetic analysis of RA receptor
gene function by establishing mutations in these genes in the mouse
germ line. Our mutation in the RAR gene14 eliminates
the major isoform of this gene, the RAR1 isoform, but leaves intact
a second product (RAR2). Our mutations in the
RARß15 and RXR16 genes completely
eliminate all products of these genes. In addition, we have
recently generated a complete loss-of-function mutation in the RXR
gene (M. Chiang, H.M. Sucov, and R.M. Evans, unpublished observations,
1997), and both isoform-specific and complete gene mutations have been
established by Kastner et al.17
When these mutations are individually bred to homozygosity, either no
apparent consequence is observed (RAR1, RARß, RAR2, and
RXR), or the phenotypes that result are confined to a
relatively small number of tissues (RAR, RAR, RXR, and
RXRß). In the developing heart, absence of RXR compromises
ventricular morphogenesis (described below) but does not
account for many of the known cardiovascular deficiency
or excess phenotypes, and no other single RA receptor gene
mutation has any cardiovascular developmental
consequence. By combining RA receptor gene mutations,17 18 19 20 21
extensive defects are seen throughout the embryo. This suggests that
the receptor genes are overlapping in expression and that the receptor
proteins are at least partially interchangeable in function, as has
been proposed for other multigene families.22 However, an
important result to emerge from these studies is the variable
frequency at which different malformations are observed with different
combinations of RA receptor gene mutations. The clear implication is
that each developmental process, in the heart and elsewhere, is
differentially sensitive to genetic manipulation.
The long-term goal of these genetic approaches is to explore the
cellular and molecular basis of the observed pathologies and of the
corresponding aspects of normal development. From an experimental
standpoint, different combinations of receptor mutations might prove to
be more or less advantageous, in terms of penetrance of
phenotypes and the presence of additional copresenting
malformations. In the present study, we have established all
possible double combinations of the RAR1, RARß, and RXR
mutations and have analyzed in detail the resultant defects in
cardiovascular development.
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Materials and Methods |
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Derivation and Analysis of Double-Mutant Combinations
Mice that are homozygous for the RAR
1 and RARß mutations
are normal and have been maintained as homozygous stocks on a mixed
genetic background in our colony. The RXR mutation is embryonic
lethal when homozygous and has been maintained as a heterozygous line
of adults. Crosses were established that yielded normal and healthy
adults of the following genotypes: [RAR1-/-, RARß-/+],
[RAR1-/+, RARß-/-], [RAR1-/-, RXR-/+], and
[RARß-/-, RXR-/+], as well as all combinations of double
heterozygotes. Appropriate animals were crossed, and embryos were
isolated at E14.5, paraffin-embedded, horizontally sectioned, and
stained with hematoxylin/eosin. Serial sections were taken from a level
above the thymus to below the bottom of the heart, and in some cases,
they were taken through the entire embryo. Yolk sac tissue was taken
for determination of genotype. |
Results |
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Embryos homozygous for the RXR
mutation, either alone or in
combination with other receptor mutations, are embryonic lethal around
E14.5, whereas RAR1/RARß double-mutant embryos survive to term.
The definitive late fetal cardiovascular organization
is largely established in normal mouse embryos by E14.5. Combination
mutant embryos in this study were therefore isolated at E14.5 and
serially sectioned to reveal defects in embryonic
cardiovascular anatomy.
Cardiovascular defects identified in this study are
summarized in Table 1
. All embryos that were double
heterozygous for any combination of receptor mutations were normal and
were not included in the data presented in Table 1.
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Atrial, Valvular, and Venous Organization
Atrial chamber defects are not among the known fetal vitamin A
deficiency phenotypes, although RA excess induces atrial septal
defects with low frequency. Defects in atrial chamber septation were
not observed, although these would have been difficult to identify at
the early time point of this study (E14.5).
Atrioventricular valve defects are also not among the
vitamin A deficiency phenotypes, although subtle
valvular defects have been documented in RXR-/- embryos by
microdissection and SEM analysis.23 These
malformations would be extremely difficult to identify in
histological sections and were not categorized in this
study. Gross abnormalities, such as persistent
atrioventricular canal, which was documented in vitamin
A deficiency and observed in other combinations of receptor
mutations,18 were not observed in the present study.
No defects in the organization of venous inflow into the heart were
noted in any receptor-deficient embryos, and such defects are not part
of the known vitamin A deficiency or excess phenotype.
Ventricular Chamber Morphogenesis
Embryonic vitamin A deficiency causes hypoplasia of the developing
ventricular chamber, resulting in a persistently
thin-walled chamber with a poorly formed interventricular
septum. This phenotype is embryonic lethal. An excess exposure
to RA in mammals has not been reported to affect
ventricular morphogenesis, although RA excess in chick
embryos results in a thickened
myocardium.8
All RXR-/- embryos exhibit ventricular
cardiomyocyte hypoplasia identical to the vitamin A
deficiency phenotype, as documented in several previous
studies.16 21 23 Almost all RXR-/+ embryos at E14.5
are anatomically normal in the ventricular chamber, and
RXR-/+ adults are viable, although isolated cases of hypoplasia in
E14.5 RXR-/+ embryos have been observed.
All of the embryos analyzed in this study that were homozygous
for the RXR mutation, in combination with any additional mutations
in the RAR1 or RARß genes, revealed ventricular
chamber hypoplasia, both in the chamber wall and in the
ventricular septum (Table 1
; see Figure 1D).
The severity of hypoplasia was comparable to our previously described
RXR-/- embryos. One embryo of six that was heterozygous for the
RXR mutation and homozygous for the RAR1 mutation was hypoplastic
in the ventricular chamber, comparable in severity to an
RXR-/- embryo, but as noted above, this has also been seen
occasionally with RXR-/+ embryos. Thus, addition of the RAR1 or
RARß mutations does not intensify or attenuate the
ventricular phenotype that is obtained by the
RXR mutation alone.
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RAR1/RARß double-mutant embryos almost invariably appeared normal
in the ventricular chamber, with well-formed muscular
interventricular septum and chamber walls, although one
atypical double-mutant embryo was affected by ventricular
hypoplasia. One [RAR1-/-, RARß-/+] embryo exhibited a very
mild manifestation of ventricular hypoplasia (not shown),
probably of marginal physiological consequence.
Thus, in general, combinations of the RAR1 and RARß gene mutations
do not result in ventricular chamber defects, although such
defects are reproducibly observed with any combination in which the
RXR gene product is absent.
Morphogenesis of the Aortic Sac
PTA represents a series of defects in the formation of the
A/P septum that leave a single outflow vessel arising from the heart.
PTA occurs rarely and only partially after vitamin A deficiency and is
infrequently, if ever, seen after vitamin A or RA excess treatment.
RXR-/- embryos have a low incidence (
10%) of PTA (see legend
to Table 1). In this study (Table 1 and Fig 2), one of
four RARß/RXR double-mutant embryos exhibited PTA, and one of five
[RARß-/+, RXR-/-] embryos displayed a localized partial
defect in the A/P septum (A/P window, Fig 2L). Because the RXR
mutation alone yields such defects in 10% of cases, the frequencies
in these classes of combination mutants do not appear to differ
significantly from those observed with RXR alone. However, PTA was
recovered in two of six [RAR1-/+, RXR-/-] embryos and in
five of six RAR1/RXR double-mutant embryos. Thus, combining the
RAR1 mutation with RXR deficiency significantly increased the
incidence of A/P septal malformation.
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PTA was also seen in all RAR1/RARß double-mutant embryos. This was
true as well for embryos examined at E18.5,20 indicating
that the underlying cause of PTA is not a delay but rather a failure in
the formation of the A/P septum. Embryos homozygous for the RXR
mutation could not be taken past E14.5 to demonstrate this same
principle because of the lethality caused by ventricular
hypoplasia.
Pediatric clinical diagnoses of PTA are subdivided into four
categories24 (see also below). All four subtypes of PTA
were recovered in the various double-mutant embryos studied, and with
the possible exception of PTA type A1, which appeared preferentially in
[RAR1-/+, RXR-/-] embryos, no obvious asymmetric
distribution of PTA subtypes with respect to RA receptor mutant
genotype was apparent in this study (Table 2).
This is not necessarily surprising, as the classification of PTA
subtypes is based on features relevant to surgical correction as well
as underlying developmental mechanisms.
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Morphogenesis of the Conotruncus
Conotruncal defects seen after fetal vitamin A deficiency include
membranous VSDs and DORV. Membranous VSDs, DORV, and transposition
(transposition-type DORV and transposition of the great arteries) are
known consequences of RA excess exposure, although transposition is
not one of the described vitamin A deficiency conditions.
Approximately 20% of RXR-/- embryos exhibit VSDs
representative of an incompletely formed conus septum
(see legend to Table 1). The frequency of the more severe DORV
phenotype is generally low in RXR-/- embryos, and RXR
heterozygotes are only rarely affected by conotruncal defects. A higher
frequency of more subtle conotruncal defects can be visualized in
RXR-/- embryos by microdissection and scanning electron
microscopy,23 but these would generally not have been
observed by histological analysis as in the
present study.
Combining the RAR1 mutation with RXR deficiency synergistically
increased the frequency and severity of conus malformations (Table 1).
All of the four diagnosable [RAR1-/+, RXR-/-] embryos
displayed deficiencies in the conus, three of which were severe (ie,
comparable to that shown in Fig 1C), and the fourth was of intermediate
severity (Fig 1D). The additional two embryos analyzed of this
genotype class were affected by PTA, which obscures evaluation
of conus defects and which were therefore not independently scored in
this study. The single RAR1/RXR double-mutant embryo that did not
have PTA exhibited transposition-type DORV, in which both outflow
vessels originated from the right ventricle, with the aorta passing
ventral to the pulmonary trunk (Fig 1E and 1F). Synergy between
the RAR1 and RXR genes was further evidenced by the recovery of
conus defects in two of six embryos homozygous for the RAR1
mutation and heterozygous for the RXR mutation (Fig 1B and 1C),
although such defects are never seen in RAR1-/- embryos and
only rarely in RXR-/+ embryos.
To a lesser extent, the RARß mutation also synergized with the RXR
mutation. Thus, conus deficiencies were evident in two of the five
[RARß-/+, RXR-/-] embryos and in two of the three diagnosable
RARß/RXR double-mutant embryos. However, three of the
[RARß-/+, RXR-/-] embryos and all of the [RARß-/-,
RXR-/+] embryos were normal in the conus, demonstrating a
significantly lower synergy compared with the corresponding
combinations of the RAR1 and RXR mutations.
Conotruncal malformations were not observed in homozygous/heterozygous
or double-heterozygous combinations of the RAR1 and RARß
mutations, and independent conus defects were not obvious when both
RAR1 and RARß were lacking. A membranous VSD was seen in all
RAR1/RARß double-mutant embryos, but this is at least in part an
obligate secondary consequence of PTA.
Aortic Arch Artery Anomalies
A broad spectrum of aortic arch arterial defects,
involving inappropriate persistence or regression of the third, fourth,
and sixth arch arteries and the pulmonary arteries, has been
described for both fetal vitamin A deficiency and excess syndromes. No
individual defect is seen uniformly, or even regularly, although some
anomalies occur more frequently than others.
The types of aortic arch artery anomalies observed in the
receptor-deficient embryos of this study were varied (Table 2).
Persistence of the right dorsal aorta, either in continuity with the
innominate artery (ie, a vascular ring) or as a retroesophageal right
subclavian artery (Fig 2G through 2I), was seen in several
genotype classes. A right arch of the aorta was seen in four
RAR1/RARß double-mutant embryos (Fig 2J and 2K); in two of these,
the left subclavian artery was supplied by a retroesophageal persistent
left dorsal aorta, whereas in the other two, a left innominate artery
was present as a derivative of the left fourth arch artery.
Abnormalities of the pulmonary arteries, either involving an
inappropriate origin of the right pulmonary artery (from the
left side of the truncus arteriosus [Fig 2J and 2K] or from the
innominate artery) or a missing left pulmonary artery, were
noted in several genotype backgrounds. An absent left
pulmonary artery generally copresented with a missing
left lung, but in one example the left lung was present and was
supplied by collateral vessels from the dorsal aorta, suggesting that
the primary defect might be in the formation of the left
pulmonary artery rather than of the left lung.
In two embryos with PTA, the left sixth arch artery, rather than the
left fourth artery, became the arch of the outflow tract, and the left
fourth arch artery regressed. In sections, this was ascertained by the
presence of a single vessel ascending from the arch of the aorta from
which the right and left carotid arteries both branched (Fig 2G through
2I). This organization is referred to as interrupted aortic arch type
B, and PTA with a left sixth aortic arch is defined as PTA type A4. In
PTA types A2 to A4, where only a single outflow vessel connects to
peripheral circulation, it has been
speculated24 that hemodynamic growth of
the fourth and sixth arch arteries are competitive processes.
Accordingly, when the left sixth arch becomes the definitive arch of
the outflow tract (type A4), the left fourth arch loses blood flow and
regresses. Similarly, when the fourth arch artery becomes the aortic
arch (types A2 and A3), the sixth arch artery regresses, evident as an
absent ductus arteriosus. In the two observed cases of PTA type A1,
where a shortened pulmonary trunk was formed distal to the
outflow valves, the ductus arteriosus was maintained.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We16 23 and others21 have previously demonstrated that one of the fetal vitamin A deficiency cardiovascular phenotypes, ventricular chamber hypoplasia, is replicated in RXR
-/- embryos with complete penetrance. Additional deficiency and
excess phenotypes, involving malformations of the conotruncus
and aortic arch arteries, were observed in RXR-/- embryos with low
penetrance, and no defects whatsoever have been observed in individual
RAR1-/- and RARß-/- embryos. In the present study, the
severity and frequency of conotruncal and aortic arch artery defects
were greatly intensified by combining the RXR mutation with the
RAR1 mutation in particular and with the RARß mutation as well.
Combining the RAR1 and RARß mutations resulted in PTA plus aortic
arch artery defects with complete penetrance. Most of the known fetal
cardiovascular vitamin A deficiency and excess
syndromes have been replicated in combinations of our RXR, RAR1,
and RARß mutations, mostly at high or complete penetrance.
Vitamin A Deficiency and Receptor Deficiency
In general, a similar spectrum of cardiovascular
defects is obtained by RA receptor mutation and nutritional vitamin A
deficiency, demonstrating that removal of ligand or receptor
compromises the same developmental processes. However, in the vitamin A
deficiency studies, aortic arch artery defects, membranous VSDs, and
ventricular hypoplasia were the prominent malformations;
PTA was seen rarely and only partially; and severe conus defects were
observed only rarely. Most likely, each aspect of
cardiovascular morphogenesis has a different threshold
to nutritional deficiency, such that ventricular and aortic
arch artery defects occur first, with more severe deficiency then
affecting the conotruncal septa. As such, because the
ventricular phenotype is midgestationally lethal
and because severe vitamin A deficiency is incompatible with pregnancy,
more substantial conotruncal septal defects might not have been
possible to recover in the nutritional studies. In fact, persistent
atrioventricular canal and pulmonary atresia
were only seen in vitamin A deficiency studies after midgestation
restoration of vitamin A,2 suggesting that these
phenotypes require extreme vitamin A deficiency to occur and
were only recovered if lethality was averted. Thus, each compartment of
the developing heart uses RA through pathways that are quantitatively
unique.
Receptor mutation distinguishes these cardiovascular
developmental processes independently. As described above, different
compartments of the developing heart are differentially compromised by
different combinations of receptor mutations, with a spectrum of
genetic sensitivity differing substantially from that of nutritional
sensitivity. For example, A/P septal defects were only marginally
recovered in nutritional studies but uniformly seen in RAR1/RARß
mutant embryos. A possible explanation for these observations might
involve different levels of receptor expression in different
compartments of the developing heart or different functional properties
of different receptors relevant to specific aspects of morphogenesis in
individual cardiovascular compartments.
Vitamin A Deficiency and Excess Phenotypes
Transposition, a consequence of malrotation of the conotruncal
septum, is most commonly associated with RA excess and was not
originally reported with vitamin A deficiency. However, the recovery of
transposition in this study, albeit in a single RAR1/RXR
double-mutant embryo, suggests that alignment of the conotruncal ridges
may also require endogenous vitamin A signaling. The
severity of vitamin A deficiency in the nutritional studies might not
have been sufficient to induce this phenotype (see comments
above).
Excess exposure to RA during defined periods of embryonic development leads to conotruncal and aortic arch malformations that overlap (although not completely so) with the vitamin A deficiency syndrome. Transposition may also be one of these phenotypes, and concordant phenotypes in other developing tissues have also been obtained after vitamin A deficiency and excess (ie, cleft palate4 25 ). This could indicate that both types of manipulation perturb the same process or that different consequences are initiated by deficiency and excess, which ultimately result in convergent dismorphogenesis. For morphogenesis of the aortic arch arteries, the temporal sensitivities to excess and deficiency are noncoincident,2 4 suggesting that different consequences are elicited by each treatment, although little evidence is available for other malformations.
Paradigms of Congenital Cardiovascular Disease
The recovery of the known vitamin A deficiency and excess
cardiovascular phenotypes in the
double-receptor mutants described here illustrates the somewhat obvious
conclusion that vitamin A signaling is mediated by the vitamin A
receptors. The real significance of this effort, however, is that
genetically defined experimental models are available to uncover the
mechanistic basis of these phenotypes and of the normal
processes that underlie them. Thus, ventricular chamber
defects are specifically recovered with complete penetrance in
RXR-/- embryos, and A/P septal defects are recovered with complete
penetrance and specificity in RAR1/RARß embryos. Conotruncal
defects are recovered in high penetrance in [RAR1-/+,
RXR-/-] embryos (although with the added experimental
complications of ventricular chamber and A/P septal defects
as well). We have recently determined (M. Chiang, H.M. Sucov, and R.M.
Evans, unpublished observations, 1997) that combining a newly
established mutation in the RXR gene with the RXR mutation yields
conotruncal and ventricular defects with complete
penetrance and without an increase in the frequency of PTA. Other
investigators have also described additional combinations of RA
receptor gene mutations that yield cardiovascular
defects at various frequencies.18 21 Through further
analysis of these lines of mice, molecular and cellular
paradigms might be obtained to explain the etiology of the observed
murine defects and possibly of the corresponding defects in humans as
well. These genetic models should be of great usefulness in pursuing
the fundamental bases of normal and pathological
cardiovascular development.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by grants to Dr Sucov from the American Heart Association (No. 96012100) and the American Heart Association, Greater Los Angeles Affiliate, Inc (No. 1118-GI1); to Dr Giguere from the Medical Research Council of Canada (No. MA-10561) and the National Cancer Institute of Canada (No. 1662); and to Dr Evans from the National Institutes of Health (GM-26444), the Mathers Foundation, and the Howard Hughes Medical Institute.
Received October 15, 1996; accepted March 6, 1997.
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References |
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