© 1998 American Heart Association, Inc.
Rapid Communications |
Cardiac Myosin Binding Protein C Gene Is Specifically Expressed in Heart During Murine and Human Development
From the Laboratoire d'Histo-Embryologie et de Cytogénétique (F.F.), Faculté Cochin Port-Royal, Paris, France; Service d'Histo-Embryologie et de Cytogénétique (A.-L.D.), Hôpital Necker, Paris, France; the Généthon (F.F., J.S.B.), URA1922 C.N.R.S., Evry, France; the INSERM Unit 153 and the IFR de Physiopathologie et Génétique Cardiovasculaire (M.Y.F., K.S., L.C.), Groupe Hospitalier Pitié-Salpétrière, Paris, France.
Correspondence to Dr Lucie Carrier, INSERM UR153, Institut de Myologie, Rue du Mur des Fermiers Généraux, Groupe Hospitalier Pitié-Salpétrière, 47 boulevard de l'Hôpital, 75651 Paris cédex 13, France. E-mail lcarrier{at}myologie.infobiogen.fr
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Abstract |
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Abstract—Cardiac myosin binding protein C (MyBP-C) is a substantial component of the sarcomere, with both structural and regulatory roles. The gene encoding cardiac MyBP-C in humans is located on chromosome 11p11.2, and mutations that are most predicted to produce truncated proteins have been identified in this gene in unrelated families with familial hypertrophic cardiomyopathy (FHC). To understand better the pathophysiology of FHC and with a view to the development of animal models for this disease, we have investigated by in situ hybridization the pattern of expression of the cardiac MyBP-C gene during human and mouse development using species-specific oligonucleotide probes. From 4 weeks of human development, a strong labeling of cardiac MyBP-C mRNAs was unambiguously detected in all heart compartments, and no signal could be visualized in somites. In murine embryos, from embryonic day 9.5 until birth, a strong signal was detected exclusively in the heart. Our results showed that during both human and murine development, in contrast to chicken development, the cardiac MyBP-C gene is abundantly and specifically expressed in the heart.
Key Words: myosin binding protein C • cardiac muscle • mouse development • human development • expression
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Myosin binding protein C (MyBP-C) is a substantial component of the striated muscles located in the C zone of the A band of the thick filament of the sarcomere. Three isoforms have been identified in adult striated muscle: a fast skeletal, a slow skeletal, and a cardiac isoform.1 2 For a decade, several lines of evidence have pointed to a potentially important structural and regulatory role of MyBP-C in the sarcomere. MyBP-C participates in the assembly of the thick filaments in striated muscle through several protein-protein interactions: it is intimately associated with myosin subfragment-2 and light meromyosin3 ; it competes with myosin subfragment-1 for binding to F-actin, which results in a modulation of the myosin ATPase activity4 5 ; and last, it binds to titin (or connectin).6 7 The addition of MyBP-C modulates the actin-activated ATPase activity of skeletal and cardiac myosins5 8 9 ; conversely, partial extraction of MyBP-C from rat skinned cardiac myocytes and rabbit skeletal muscle fibers alters Ca2+-sensitive tension.10 Cardiac MyBP-C is phosphorylated under adrenergic stimulation,11 12 13 and it was recently shown that this phosphorylation alters myosin crossbridges in native thick filaments isolated from rat ventricles, suggesting that MyBP-C can modify force production in activated cardiac muscles.14 Finally, several mutations in the gene encoding the cardiac isoform in humans (MYBPC3) have been identified in unrelated families with FHC.15 16 17
FHC is an autosomal-dominant disease characterized by a ventricular hypertrophy predominantly affecting the interventricular septum and associated with a large extent of myocardial and myofibrillar disarray. It is the most common cause of sudden death in young athletes. Many forms of the disease involve mutations in genes encoding sarcomeric proteins (for reviews, see References 1818 to 20), and the finding that MYBPC3 is one of these disease genes markedly strengthens the hypothesis that cardiac MyBP-C plays an important role in the regulation of cardiac contraction in health and disease. Major insights into the functional consequences of the mutations and the pathogenesis of FHC were obtained through analysis of skeletal muscle biopsies of FHC patients with mutations in the ß-MHC gene.21 22 This approach could be achieved because the ß-MHC gene is normally expressed in both cardiac and slow-twitch adult skeletal muscles (see Reference 2323 for a review). This is not the case for the cardiac MyBP-C gene: it is not expressed in adult skeletal muscles, and human cardiac biopsies are seldom available. In chickens, it was shown that cardiac MyBP-C is transiently expressed in embryonic skeletal muscles.24 25 26 We have investigated by in situ hybridization the pattern of expression of the cardiac MyBP-C gene during human development with the idea that if this gene is transiently expressed in embryonic and/or fetal skeletal muscles, satellite cells from adult skeletal muscles could be used as a model system to analyze in vitro the transcription, the translation, and the function of cardiac MyBP-C. The expression of the titin gene was used as a control of skeletal muscle development. Furthermore, with a view to the development of animal models for FHC, we have also analyzed the pattern of expression of the cardiac MyBP-C gene in mice.
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Materials and Methods |
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Human Tissues
Normal human embryos (from 4 to 7 postovulatory weeks) were obtained from legal abortions induced by mifepristone (RU486) at the Broussais Hospital in Paris. All procedures were approved by the Ethical Committee of the Necker-Enfants Malades Hospital in Paris. Each sample was first observed macroscopically during dissection under a stereomicroscope; the developmental stage of the embryo was determined using established criteria.27 The heads and spinal cords of the 10- to 12-week-old fetuses were not available for analysis. Fetal human hearts at 15, 17, and 21 weeks of development were also included in this study.
Murine Tissues
Murine embryos of the NMRI strain, from 9.5 days post coitum to
birth were examined. Tissues were collected shortly after delivery and
frozen within the first 24 hours post mortem in dry ice and stored at
-80°C until used. Ten-micron-thick cryostat sections were mounted on
slides previously coated with a 2% 3-aminopropyltriethoxysilane
solution in acetone. The sections were postfixed for 20 minutes in 2%
paraformaldehyde in a 0.1 mol/L phosphate buffer (pH
7.4) at room temperature, rinsed (once for 2 minutes) in a phosphate
buffer, rinsed briefly in water, and dehydrated with a series of washes
in ethanol solutions (50%, 75%, and 100%). The sections were then
air-dried and finally stored at -80°C. The integrity of each embryo
was checked using conventional histological and
histochemical staining techniques.
Oligonucleotide Probes
Purified 60mer oligonucleotide antisense cardiac
MyBP-C cDNA probes were determined according to either the human
sequence (EMBL accession number X84075), 5'-AAC ACG GCA GGG CTG CCT GCG
GCC ACT TCC ACT GAC CGT GGC TTC TTG CTA AAG GCT GAG-3', or the murine
sequence,28 5'-ACA CGG CAG CAC TGC CAG CAG TCA
CCT CCG CTG ACC TTG GCT TCT TGT TGA AGG CTG ACA-3'. These probes were
chosen in the 5' cDNA sequence in order to recognize only the cardiac
variant. The probe specific to the titin gene was chosen in the A-band
sequence in order to recognize both the cardiac and skeletal isoforms
as described by Fougerousse et al.29 Control sense probes
were chosen from the opposite cDNA strands.
Northern Blot Analysis
All oligonucleotide probes (100 ng) were 5'
end–labeled with [
-32P]ATP (New England
Nuclear) using T4 polynucleotide kinase (Promeg) for 1.5
hours at 37°C and then separated from the free
nucleotides by chromatography on Biospin 6
columns (Bio-Rad). Mouse and human multiple-tissue Northern blots
(Clontech) were prehybridized for 30 minutes at 65°C with ExpressHyb
hybridization solution (Clontech). Hybridizations were performed at
65°C for 1.5 hours with the corresponding probes
(1x106 cpm/mL). The blots were washed for 20
minutes in 2x SSC and 0.1% SDS at room temperature and for 20 minutes
in 0.1x SSC and 0.1% SDS at 37°C. The blots were then exposed to
X-Omat film (Kodak) at -80°C for several hours.
In Situ Hybridization
All probes were 3' end–labeled with
[
-35S]dATP (Dupont-Nemours) using terminal
deoxyribonucleotidyl transferase (BRL) and purified on Biospin columns
(Bio-Rad). The in situ hybridization medium contained 50% formamide,
4x SSC, 1x Denhardt's solution, 0.25 mg/mL sheared salmon sperm DNA,
0.25 mg/mL polyA, 0.25 mg/mL tRNA, 10% dextran sulfate, 100
mmol/L DTT, and [-35S]dATP–labeled probe
(6x106 cpm/mL). One hundred microliters of the
hybridization solution was deposited on each section, which was then
covered with a parafilm coverslip and incubated in a humidified chamber
at 43°C for 20 hours. After hybridization, the sections were washed,
twice for 15 minutes each at 55°C in 1x SSC containing 10
mmol/L DTT, twice in 0.5x SSC containing 10 mmol/L DTT, and
finally in 0.5x SSC containing 10 mmol/L DTT at room temperature.
The sections were then dehydrated with a series of graded
concentrations of ethanol, exposed to Amersham Betamax x-ray films for
12 days, and then dipped in Kodak NTB-2 nuclear track emulsion and
exposed for 2 months before development. The sections were examined
using a Zeiss Axiophot microscope. Negative controls of in situ
hybridization were tested with the sense probes on adjacent slides.
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Results |
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Northern blot analysis of polyA+ RNA isolated from several adult murine and human adult tissues with the cardiac-specific MyBP-C oligonucleotide probes showed that an mRNA of
4.5 kb was detected abundantly in cardiac muscle,
although it was absent in skeletal muscle, brain, spleen, lung, liver,
kidney, and testis in both humans and mice (data not shown). The size
and tissue specificity of this mRNA are in full agreement with previous
cloning data,11 28 and this clearly shows that
the chosen oligonucleotide probes are specific to the
cardiac MyBP-C isoform in both animal species.
At 4 weeks of human development (Fig 1A
through 1D), a strong labeling of cardiac MyBP-C mRNAs was
unambiguously detected in the whole embryonic heart (Fig 1B). No signal
could be detected in the myotome compartment (Fig 1B). No signal was
detected with the human control sense probe (Fig 1D). In contrast,
titin mRNAs were clearly present both in the heart and in the
myotome compartment (Fig 1C). In 10- to 12-week-old fetuses (Fig 1E
through 1G), cardiac MyBP-C mRNAs were detected throughout the
four-chambered heart (Fig 1F). At this stage, cardiac MyBP-C mRNAs were
not expressed in fetal skeletal muscles, whereas titin mRNAs were
detected at significant levels (Fig 1G). Transcription of the cardiac
MyBP-C gene persisted uniformly in the later hearts studied but was not
present in skeletal muscles (15, 17, and 21 weeks old) (data not
shown).
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Sagittal sections of murine embryos were investigated systematically
with the cardiac MyBP-C oligonucleotide probe from E
9.5 to E 18.5 (Fig 2). At E 9.5, the
primitive heart tube was strongly and specifically labeled (Fig 2D). No
signal was detected with the murine control sense probe (Fig 2E). This
cardiac-specific pattern of hybridization was also seen at E 10.5 and E
18.5 (Fig 2F and 2G), without any expression of the cardiac MyBP-C gene
in skeletal muscle territories.
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Discussion |
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The present study is the first analysis of the expression pattern of the cardiac MyBP-C gene during human and murine development. We show that the message for cardiac MyBP-C is detected in the ventricles and atria at very early stages in both human and mouse development, but we did not find any expression of the cardiac MyBP-C gene during skeletal muscle development. Furthermore, using reverse-transcriptase polymerase chain reaction, we were unable to detect cardiac MyBP-C transcripts during the differentiation of C2-C12 skeletal muscle cells in culture, hence confirming that there is no expression of cardiac MyBP-C gene in skeletal muscle (data not shown). This result is at variance with what has been described in the chicken: it was found that cardiac MyBP-C is expressed in both cardiac and skeletal muscle during embryonic development.24 25 26 This probably reflects a difference in the organization of the promoter region of the avian and the mammalian genes. After the embryonic stages in chicken skeletal muscles, cardiac MyBP-C is replaced subsequently by both slow skeletal and fast skeletal isoforms in late embryonic development, after which the slow skeletal isoform disappears and only the fast skeletal isoform persists during postnatal development. Two splice variants of the cardiac MyBP-C gene were found in chicken development, and further investigations will be required to determine whether splice variants also exist in mammals. Nevertheless, it is reasonable to assume that even if several variants are transcribed from the human and murine cardiac genes, they would follow the same pattern of expression.
The appearance of the sarcomeric protein gene transcripts that interact
directly or indirectly with MyBP-C in the newly formed cardiac tube is
very similar to that reported in the present study for cardiac
MyBP-C. In humans, the ß-MHC, cardiac -actin, and titin genes are
expressed at a high level in the embryonic heart from 4 weeks of
development (the present study, Reference 3030 , and, for a review,
Reference 2323 ). In the mouse embryo, mRNAs encoding ß-MHC, titin, and
cardiac -actin are all detected at high levels at 8 days post coitum
(for review, see Reference 3131 ). One might thus hypothesize that the
potential impairment of sarcomerization associated with FHC occurs very
early during development for the two major causative genes, ß-MHC and
cardiac MyBP-C. In this context, mice expressing the ß-MHC mutant are
good models for FHC.32 33 Since the cardiac
MyBP-C gene is expressed uniquely in the heart, it is clear that
analyses of the consequences of the mutations at molecular and
cellular levels will not be possible in human skeletal muscle biopsies
and that animal models will be needed. Our present results suggest
that the expression of cardiac MyBP-C mutants in mice should also
resemble the expression in human disease and will help to resolve the
pathogenesis of FHC.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the Association Française contre les Myopathies. We are grateful to Drs E. Aubini, J.-H. di Donato, and R. Taurelle for providing human fetuses and embryos and to Muriel Durand and Laurence Suel for their technical assistance. We also thank Gisèle Bonne and Sophie Venin for fruitful discussion.
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Footnotes |
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This manuscript was sent to Laurence H. Kedes, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received July 1, 1997; accepted November 7, 1997.
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References |
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