© 1999 American Heart Association, Inc.
Original Contribution |
Replacement by Homologous Recombination of the minK Gene With lacZ Reveals Restriction of minK Expression to the Mouse Cardiac Conduction System
From the Departments of Medicine (S.K., T.Y., M.E.A., M.A.M., D.M.R.), Pharmacology (S.K., T.Y., M.E.A., D.M.R.), and Molecular Physiology & Biophysics (K.D.N., M.A.M.), Vanderbilt University School of Medicine, Nashville, Tenn, and Department of Cell Biology and Anatomy (A.W.), Medical University of South Carolina, SC.
Correspondence to Dan M. Roden, MD, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Medical Research Building I, 532C, Nashville, TN 37232-6602. E-mail dan.roden{at}mcmail.vanderbilt.edu
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Abstract |
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Abstract—The minK gene encodes a 129-amino acid peptide the expression of which modulates function of cardiac delayed rectifier currents (IKr and IKs), and mutations in minK are now recognized as one cause of the congenital long-QT syndrome. We have generated minK-deficient mice in which the bacterial lacZ gene has been substituted for the minK coding region such that ß-galactosidase expression is controlled by endogenous minK regulatory elements. In cardiac myocytes isolated from wild-type neonatal mice, IKs is rarely recorded, while IKr is common. In minK (–/–) myocytes, IKs is absent and IKr is significantly reduced and its deactivation slowed; these results further support a role for minK in modulating both IKs and IKr. Despite these changes, ECGs in (+/+) and (–/–) animals are no different at adult and at neonatal stages. ECG responses to isoproterenol are also similar in the 2 groups. ß-Galactosidase staining in postnatal minK (–/–) hearts is highly restricted, to the sinus-node region, caudal atrial septum, and proximal conducting system. Moreover, as early as embryonal day 11, segmentally restricted ß-galactosidase expression is observed in the portions of the sinoatrial and atrioventricular junctions that are thought to give rise to the conducting system, thereby implicating minK expression as an early event in conduction system development. More generally, the restricted nature of minK expression in the mouse heart suggests species-specific roles of this gene product in mediating the electrophysiological properties of the heart.
Key Words: K+ current • conducting system • development • delayed rectifier
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Introduction |
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The congenital long-QT syndrome (LQTS) is characterized by prolongation of cardiac repolarization, ventricular arrhythmias, and sudden death.1 2 LQTS is most commonly caused by mutations in HERG or KvLQT1, which encode the structural (
) subunits for the channels underlying
the cardiac delayed rectifier currents IKr
and IKs,
respectively.3 4 5 These 2 pharmacologically and
physiologically distinct currents were
originally described in guinea pig heart6 and have since
been observed in human heart.7 8 The rapidly activating
component (IKr) is sensitive to specific
blockers such as dofetilide or E4031, and the slowly activating one
(IKs) is augmented by
catecholamines.6 9 The minK (or IsK) gene encodes a small protein (129 amino acids in mouse and human) that modifies the currents resulting from expression of HERG or KvLQT1. The potassium currents resulting from expression of KvLQT1 alone are small and activate very rapidly, but IKs is reconstituted when minK is coexpressed with KvLQT1.10 11 Whereas IKr can be recapitulated by expression of HERG alone,4 12 both antisense and coexpression studies suggest that minK augments IKr (HERG-mediated current) without altering its gating.13 14 Mutations in the minK gene have been reported as a rare cause of LQTS.15
One phenotype of mice in which the minK gene has been disrupted is a striking movement disorder attributed to a defect in endolymph transport in the inner ear.16 Drici et al17 have recently reported that in these mice, QT interval prolonged to a greater extent at slow rates (seen with prolonged anesthesia) compared with that in wild-type (wt) mice. The present experiments were conducted in mice in which the minK gene was disrupted and the lacZ gene was included in the targeting vector, such that staining for ß-galactosidase expression in minK (–/–) animals would report the pattern of minK expression. Our results indicate normal ECGs at physiological and isoproterenol-stimulated rates in the knockout mouse and suggest unexpectedly restricted minK expression in the heart as an underlying mechanism.
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Materials and Methods |
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Isolation of the minK Genomic Clone
Four independent overlapping clones covering
20 kb of
the minK locus were isolated by screening
106 plaques from a 129SV genomic library in
Lambda Fix II (Stratagene) under high-stringency conditions
using as a probe the minK cDNA sequence in plasmid T21 (a
gift of Dr Mike Tamkun, Colorado State University, Fort Collins,
Colo). Library screening, DNA purification, restriction enzyme mapping,
and subcloning were performed using standard
procedures.18
Construction of the Targeting Vector
A 6.2-kb EcoRI/XhoI fragment
covering exon 2 (which includes the complete coding region of the
minK gene19 was subcloned into the
Bluescript II KS– vector (Stratagene). The
XbaI site was deleted from the polylinker of the vector
after digestion by treatment with Klenow enzyme, and 2 unique
XbaI sites were introduced flanking the minK coding exon
with the use of the Kunkel method of site-directed
mutagenesis.20 The oligonucleotide
used to introduce the upstream site (5'-CGTCAAGGTT
CCCCGGATCT AGAGCAAAAC TCC-3') is located 28 bases 5' of the
initiator ATG of the minK gene. The
oligonucleotide used to introduce the downstream
XbaI site (5'-CCGCTTGTCA CCTCTAGAGT GTGGGGTTCA
CGAC-3') is located 11 bases 3' of the stop codon. Bases that mutate
the minK sequence are underlined. With introduction of these
sites, the minK coding region could then be excised in its
entirety (total deletion of 427 nt) by digesting the plasmid with
XbaI. Religation created a plasmid (pSKII120) that included
a unique XbaI site that was then used to accept the
lacZ-neor cassette described below.
Consensus splice sites of exon 2 were conserved throughout all
manipulations.
The PGK (phosphoglycerate kinase-1)-neo-pA gene was excised from plasmid pPNT21 via NotI/KpnI digestion. In its place, the minK targeting locus from pSKII120 was inserted, taking advantage of NotI/KpnI sites of its flanking polylinker. The resulting plasmid pSKII147/4 contained the thymidine kinase (TK) gene at the 3' end.
Concurrently, a cassette was engineered that contained the
neomycin resistance (neor) gene driven by PGK
promoter of pPNT into the vector pSL1180 (Promega). The lacZ
gene of pPD46.21, which has an initiator ATG codon and contains a
nuclear localization signal at the 5' end (a gift of Dr Thomas
Quertermous, Stanford University, Palo Alto, Calif), was then
added to the 5' end of the insert. The
lacZ-neor cassette was flanked by
XbaI sites that were used for excision of the cassette and
its subsequent insertion into the unique XbaI site of
pSKII147/4. This manipulation separated the minK targeting
locus into a 4.2-kb long arm and a 1.6-kb short arm homologous to the
wt minK locus and put the lacZ gene under the
control of endogenous minK regulatory elements
after gene targeting (Figure 1A
).
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Gene Targeting
Fifty micrograms of linearized, purified vector DNA was
electroporated into 50x108 embryonic stem (ES)
cells at 800 V, 3 µF. The TL1 line of ES cells was
used.22 Cells were plated onto irradiated
neomycin-resistant feeder cells and selected in G418 and
ganciclovir. Colonies were harvested and screened using standard
procedures.23
Genomic Southern Analyses
DNA obtained from ES cells23 was digested with
XbaI, Southern blotted using standard
protocols,18 and probed. Mice were genotyped
for correct targeting by preparing tail DNA of 3-week-old
weanlings.23 The 5' probe consisted of a 600-bp
restriction fragment that immediately abuts the XbaI site 5'
of the targeting locus (Figure 1A
). With this probe,
hybridization is predicted to yield an 8-kb XbaI
fragment from the wt locus and a 5.8-kb fragment for the correctly
targeted allele. The 3' probe consisted of the 400-bp
XhoI/XbaI fragment immediately 3' of the
targeting locus (Figure 1A). With this probe, the same 8-kb band
is expected in the wt case, while a 2-kb band is expected for the
targeted allele.
To verify that there was only a single insertion event per genome, a Southern blot of mouse genomic DNA cut with EcoRI was probed with an internal probe consisting of a 265-bp PCR fragment from the 5' end of the lacZ gene. A single 7.8-kb fragment was expected, if targeting occurred correctly.
RNase Protection Analysis
RNase protection was performed using standard
methods.13 The riboprobe was complementary to the mouse
minK cDNA, lacking the 5' 70 coding
nucleotides.
ES Cell Microinjection and Mouse Husbandry
Targeted ES cell clones from 129SV mice were microinjected into
the blastocoel cavity of embryos derived from natural matings of
C57BL/6 mice. The resulting chimeras were bred to 2 different strains
of mice, Black Swiss and 129SV (Taconic). The studies reported here
were all conducted using the inbred 129SV mice; however, we have
observed similar findings with the other strain. Mice were housed in
microisolator cages on a 12 hours light/12 hours dark cycle and were
specific pathogen free. Animal care principles were followed as
outlined in the National Institutes of Health Guide for the Care
and Use of Laboratory Animals.
ECGs
Adult animals were anesthetized with ketamine
(30 mg/kg) and pentobarbital (38 mg/kg), as described by Berul et
al.24 A jugular vein was cannulated for administration of
isoproterenol. In neonatal animals, ECGs were obtained in the drug-free
state from littermates resulting from (+/–)x(+/–) matings; these
animals were then euthanized and genotyped as described
above. Animals were kept on a heating pad set at 38°C. Clips were
attached to all 4 limbs, and recordings were obtained with
filtering at 3 to 100 Hz using an analog ECG recorder (E/M VR16). A
paper speed of 100 mm/s was used, and tracings were
analyzed offline by an investigator blinded to genotype
using a digitizing tablet and custom-written software. For each ECG, 3
consecutive complexes were analyzed in lead aVR, in which the
onset and end of the intervals are easiest to distinguish.
Neonatal Mouse Cardiac Myocyte Dissociation
Neonates were deeply anesthetized with isoflurane
and euthanized by cervical dislocation. Hearts were removed and placed
in prewarmed ADS buffer. Each heart was washed free of blood,
and the atria and ventricles were dissected into 2- to 3-mm pieces.
Buffer was removed by brief centrifugation, and fresh
buffer with collagenase type II (0.5 mg/mL) and pancreatin
(1 mg/mL) was then added. Digestion was performed at 37°C for 15
minutes, after which tubes were quick spun and the supernatant was
transferred to DMEM supplemented with 10% horse serum and 5% FBS and
placed in a 5% CO2 incubator.
Electrophysiological Study Procedures
Standard methods were used to record whole-cell
potassium currents at room temperature during and following 0.5- to 5-s
pulses to a range of depolarizing potentials. The extracellular
solution was Tyrode's solution with 1 µmol/L nisoldipine added
to block L-type calcium current and depolarized holding potentials
(–40 mV) to inactivate sodium current and T-type calcium
current (which we have previously observed in mouse atrial
cells).13 25 IKr was
readily recognized as a rapidly activating outward current displaying
prominent inward rectification and large, deactivating tail
currents.6 25 26 IKs was
defined as slowly activating and deactivating outward current
recorded in the presence of dofetilide and displaying ohmic or
outwardly rectifying properties. All currents were normalized to cell
size, which was determined by recording the capacitative
current (before compensation) elicited by a voltage-clamp step from
–80 to –70 mV. Individual cell capacitance was then calculated as
Q/V=
Idt/V=Idt/10,
where Q is charge, I is current, and V
is the magnitude of the voltage step (10 mV).
Staining for ß-Galactosidase (lacZ)
Activity
Organs were fixed at 4°C for 1 hour in 4%
paraformaldehyde made up in 0.1 mol/L phosphate buffer
(pH 7.3), 5 mmol/L EGTA (pH 8.0), and 2 mmol/L
MgCl2 (fixative) and then washed for 15 minutes
at 4°C with PBS (8 g NaCl, 0.2 g KCl, 1.44 g
Na2HPO4, and 0.24 g
KH2PO4 to 1 L in
H2O, pH 7.4). They were then
permeabilized in 0.1 mol/L phosphate buffer (pH 7.3),
2 mmol/L MgCl2, 0.01% sodium deoxycholate,
and 0.02% NP-40 in 3 steps of 15 minutes each, at room temperature.
Samples were then stained in the permeabilization solution plus 1 mg/mL
X-Gal, 5 mmol/L potassium ferricyanide, and 5 mmol/L
potassium ferrocyanide in the dark at room temperature. Staining times
varied with sample size. Samples were then briefly washed in PBS
followed by a postfix step in fixative for 1 hour and stored in 70%
ethanol until use.
Connexin40 (Cx40) Staining of lacZ-Stained
Mouse Hearts
ß-Galactosidase–stained mouse hearts were dehydrated
through 50%, 70%, 95%, and 100% ethanol into 100% isopropanol and
then paraffin embedded. The hearts were then sliced into 5-µm
sections and deparaffinized through 2 changes of xylene and 1 change
each of 100%, 70%, and 50% ethanol for 2 minutes each. Slides were
then washed in water followed by boiling in 10 mmol/L citrate
buffer, pH 6.0, in a microwave oven 3 times for 2 to 3 minutes at an
80% power setting. They were then incubated for 30 minutes at room
temperature in blocking buffer (1% BSA [essentially globulin free;
Sigma], 0.3% Triton X-100, and 3% goat serum). Anti-Cx40 antibody (a
gift of Dr Jeffrey Saffitz, Washington University, St. Louis,
Mo) was diluted 1:200 into blocking buffer and reacted with the
slides overnight at 4°C. The slides were then rinsed extensively with
PBS followed by a 2-hour incubation with a 1:400 dilution of
Cy3-conjugated goat anti-rabbit IgG (Jackson ImmunoResearch
Laboratories, West Grove, Pa). Samples were analyzed on a Leica
microscope with standard epifluorescence.
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Results |
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Gene Targeting
Southern blotting of genomic DNA derived from ES cells selected under G418 and ganciclovir as well as from offspring of chimeric (and later-generation) animals demonstrated single inserts of the appropriate size and thus germline transmission. RNase protection analysis demonstrated that minK mRNA was absent in (–/–) animals (Figure 1B
).
ECGs and K+ Currents
Homozygous null animals displayed the movement disorder previously
reported.16 ECGs in adult wt and minK (–/–)
mice (Figure 2A) showed no difference in
any interval; specifically, the QT interval was identical in the 2
groups. Moreover, with infusion of isoproterenol, the increase in heart
rate (shortening of R-R interval) and shortening of QT intervals were
also similar in the 2 groups. In adult mouse heart (unlike in humans),
the major repolarizing current is
ITO,27 the rapidly
inactivating transient outward current, the increasing expression of
which during postnatal development shortens action potential duration.
However, IKr and
IKs have been reported to be prominent in
cultured neonatal mouse heart cells.28 29 30 We
therefore recorded ECGs in neonatal animals and recorded
outward currents in acutely disaggregated cardiac cells isolated from
2- to 3-day-old mice. As shown in Figure 2B, neonatal ECGs were
no different in wt and (–/–) animals. QT intervals were longer in
neonates (85 to 93 ms) than in adults (60 to 81 ms) regardless of
phenotype, consistent with previously reported
action-potential–duration data.27
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Whereas IKr was readily recorded in
neonatal cells from both wt and (–/–) animals (Figure 3A), it was less frequently recorded
in the knockout (11/48 [23%] versus 39/48 [81%] cells;
P=0.004). The example shown in Figure 3A suggests
that IKr deactivation was slower in (–/–)
compared with wt animals. Indeed, in wt animals, the deactivating tail
was best fit by 2 exponentials (eg, 97±7 and 594±33 ms after a pulse
to +20 mV); by contrast, deactivation was best fit by a
monoexponential (648±65 ms) in the (–/–) animals.
Current-voltage relations, presented in Figure 3B for
cells in which surface area was also recorded, demonstrate that the
amplitude of IKr in minK (–/–)
mice was also significantly smaller than that in the wt animals.
IKs was only very infrequently recorded
in acutely disaggregated neonatal mouse myocytes (4 of 45 cells, 9%)
and was not recorded in >50 cells studied from (–/–) animals.
Unlike IKr and
IKs, the amplitude of the transient outward
current (ITO), which was detected in all
(16 of 16) neonatal myocytes subjected to depolarizing clamp steps from
a holding potential of –80 mV, was similar in the 2 groups (eg,
14.4±2.2 pA/pF at +40 mV in wt animals versus 12.3±2.5 in the
[–/–] animals; n=8 each, P=NS).
ITO inactivation was biexponential, and the
time constants were also no different (48.1±5.5 versus
45.1±9.4 ms [
1]; 116±27 versus 124±31 ms
[2]; wt versus [–/–] respectively).
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ß-Galactosidase Staining
In adult animals, there was virtually no ß-galactosidase
staining in the ventricles (Figure 4A).
However, consistent areas of dense staining were observed in
the sinus-node region, on the caudal aspect of the right atrial septum
and in the subaortic region of the left atrial septum, in the region of
the atrioventricular node, and in the proximal
conducting system (Figure 4A through 4D).
Ventricular endocardial ß-galactosidase staining
colocalized with immunostaining against a connexin
isoform (Cx40) expressed specifically in the mouse conducting system
(Figure 4E and 4F)31 and not in working myocytes.
The staining patterns were similar in (+/–) animals, and no staining
was observed in wt animals.
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In the day 11 embryo, ß-galactosidase staining was most
prominent in heart, although some staining in the developing brain was
also observed (Figure 5A). However, it is
apparent that even at this stage, minK expression in the
heart was already restricted, with especially intense ß-galactosidase
staining in the outflow tract and in the interventricular
junction (Figure 5B). Less intense staining was observed in the
upper regions of both left and right ventricles, and only very little
staining was observed in the apical regions of the embryonic
ventricles. No surface staining was observed in the atria at this stage
of development. Histological inspection of the serial
cardiac sections showed staining circumferentially around the
atrioventricular canal (Figure 5C), staining in
the sinoatrial region (ie, staining in the left and right venous valves
and in the septum spurium), and staining in the leading edge of the
primary interatrial septum. Although most of the stained cells were
myocytes, blue nuclei were also occasionally observed in endocardial
cells (in particular in the distal outflow tract) and in mesenchymal
cells in the endocardial cushions.
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Discussion |
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In humans, mutations in minK have been associated with prolongation of the QT interval.15 However, we did not observe any difference in baseline QT (73±11 ms versus 73±16 ms; wt versus minK [–/–]) or R-R intervals (134±11 versus 138±29), nor was there any difference in QT when heart rate was increased by isoproterenol (Figure 2B
). By contrast, at similar
R-R intervals, Drici et al17 found slightly longer QT
intervals in wt animals (
90 versus 70 ms) and a greater
difference as heart rate slowed during prolonged
anesthesia; like us, they also reported no difference in QT
intervals at fast rates after isoproterenol, which they administered
intraperitoneally. However, both we and Drici et
al17 found IKs in only 10%
of cultured neonatal cells from wt animals and in no cells from
minK (–/–) mice. This is consistent with the
restricted expression of minK that we have now reported.
Since the currents determining total repolarization time in adult mice
are different from those in humans,27 we believe our
ECG data are consistent with the idea that, by birth,
IKs and IKr do
not play an important role in determining repolarization in mice; it
may be that inactivation of the very prominent L-type calcium channel
is the dominant factor.29 Thus, the mechanism
underlying the ECG findings of Drici et al17 will require
further study; possibilities include a role for
IKs or another minK-mediated
current (in only a minority of cells) in rate dependence of
repolarization or a differential effect of anesthesia. The
baseline differences between the 2 studies may reflect in part the
different high-pass filters (3 versus 0.1 Hz) used. In cultured mouse atrial cells, anti-minK antisense oligonucleotides reduced the amplitude (but not the gating) of IKr,13 and coexpression of minK with HERG has been shown to increase IKr amplitude without modifying its gating.14 Thus, the reduction in IKr amplitude we observed in minK (–/–) mice is consistent with the hypothesis that minK interacts with the murine ERG product to modify IKr in a subpopulation of cells. Further, the slowing of IKr deactivation that we observed in minK (–/–) animals (while not observed in previous experiments)13 14 also lends strong support to the concept that minK modifies ERG function. Drici et al17 did not report a difference in IKr amplitude or gating in minK (–/–) mice, although the examples presented do suggest slower deactivation in the knockout mice (their Figure 6). The mechanism underlying such a difference in deactivation is unknown but is highly reminiscent of that observed when a cardiac-specific murine ERG splice isoform is expressed with the originally described cDNA32 33 ; thus, suppression of expression or function of this splice variant may be occurring in the minK knockout mice. Studies to examine this hypothesis are in progress; it is worth noting that previous work, in an atrial cell line and in Xenopus oocytes, could not reveal this difference, because the relevant splice isoforms are not part of those experimental paradigms. Failure of expression of a cardiac-specific isoform of ERG might also underlie the reduction in proportion of cells expressing IKr; another possibility is that the lack of minK associated with ERG channels results in a failure of the channel complexes to reach the cell surface.
minK expression in the developing mouse heart shows a
pronounced segmental pattern, with predominance in those regions of the
heart that flank the future atria and ventricles (Figure 5).
These areas have previously been identified as cardiac segments with
molecular phenotypes and
electrophysiological characteristics that
distinguish them from the "ordinary" myocardial
segments34 35 36 and are recognized as supporting
specialized (slow) conduction in the developing heart.37
These segments either become incorporated into atrial and
ventricular working myocardium and lose their
specialized characteristics or develop into the conduction system,
including the sinoatrial node, the atrioventricular
node, and the bundle branches and distal conduction system. The
segments stained by ß-galactosidase in the minK (–/–)
mice appear similar to the primary ring tissue identified in the
developing human heart by the G1N2 antibody,38 which
identifies regions that develop into the conducting system. To date, no
marker has been described that allows the study of the development of
the analogous flanking segments and conducting system in the mouse.
Thus, further studies to identify elements regulating restriction of
minK to these areas of the heart should provide important
new information of the development of the conducting system.
The staining in the sinus-node region in adult heart is consistent with reports that IKs may contribute to pacemaker function39 and also with the finding that minK mRNA is more abundantly expressed in the sinus-node region than in other regions in the ferret heart.40 Interestingly, the lower right atrial septum is a region of which the electrophysiological properties are increasingly recognized as playing a role in common reentrant arrhythmias, such as atrioventricular nodal reentrant tachycardia and common atrial flutter.41 42 The extent to which restricted minK expression in this region might contribute to development of these reentrant circuits requires further study. More generally, while the functional consequences of minK disruption in humans are likely to be different from those found in this mouse system, the electrophysiological and histological findings here are consistent with the concept that minK forms heteromultimers with multiple gene products to modulate cardiac ion currents.
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Acknowledgments |
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This work was supported in part by grants from the United States Public Health Service (HL46681, HL49989, HL03727, HL52813, and CA68485). Microscopic imaging and color plates were generated in part through the use of the Vanderbilt University Medical Center Cell Imaging Core Resource, supported by grants CA68485 and DK20593. K.D.N. was supported by the Medical Scientist Training Program (GM07347). M.E.A. is supported by an award from the Cardiac Arrhythmia Research and Education Foundation, Inc. D.M.R. is the holder of the William Stokes chair in Experimental Therapeutics, a gift of the Dai-ichi Corp. The expert advice provided by Al George and by Mike Tamkun at all points during the development of this project is greatly appreciated. We also appreciate the superb technical assistance of Holly Waldrop, Dana King, Nancy Sugg, and Aimee Phelps and the secretarial assistance of Cynthia Tillman.
Received April 14, 1998; accepted November 18, 1998.
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References |
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