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Targeted inactivation of the sodium-calcium exchanger (Ncx1) results in the lack of a heartbeat and abnormal myofibrillar organization ¹

SRINAGESH V. KOUSHIK^*, JIAN WANG^*, RHONDA ROGERS^*, DEMETRIUS MOSKOPHIDIS^*, NEVIN A. LAMBERT, TONY L. CREAZZO^*, and SIMON J. CONWAY^*,2

^* Institute of Molecular Medicine and Genetics,
Departments of Pharmacology and Toxicology and Augusta Veterans Affairs Medical Centre, and
Department of Cell Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912-2640, USA

²Correspondence: Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th St., CB2803, Augusta, GA 30912-2640, USA. E-mail: sconway{at}mail.mcg.edu

SPECIFIC AIMS

Because of the following—controversial role, early heart-specific expression patterns, lack of specific inhibitors, contradictory results obtained via antisense knockdown experiments, and differing functions assigned to Na⁺/Ca²⁺ exchanger (Ncx1) during embryonic excitation-contraction coupling—we used gene targeting to delete Ncx1, which allowed us to begin to determine the precise role of Na⁺/Ca²⁺ exchange in development of the mammalian heart.

PRINCIPAL FINDINGS

1. Ncx1-null embryos lack a spontaneously beating heart and are embryonically lethal
Heterozygous mice are grossly normal and fertile, whereas Ncx1-null embryos do not survive past 11.5 dpc. Ncx1-null 9.0 dpc embryos were of normal size and had undergone looping of the heart tube (Fig. 1a , b ). However, 10.0 dpc Ncx1-nulls were severely retarded in size, although they were still developing despite the lack of a heartbeat (Fig. 1c ), indicating that diffusion of growth factors/nutrients is not sufficient to maintain normal growth of the embryo at later developmental stages. Curiously, even through there was a drastic retardation in size of the whole embryo, when the size of the heart was measured and compared with the rest of the embryo it was evident that the heart was less affected by the lack of a circulation. This suggests that the rest of the embryo is more dependent on having a normal heartbeat for growth than the heart is itself. By 11.0 dpc the Ncx1-null embryos are extremely small (Fig. 1e ) and begin to die 11.5 dpc (no more somites added and tissue disintegration). Lethality is most likely due to a complete lack of vascular morphogenesis within the Ncx1-null yolk sac (not shown).

View larger version (101K): [in this window] [in a new window]   Figure 1. Phenotypic and histological analysis of Ncx1lacZ mutant embryos. a, b) Whole-mount lacZ staining of normal heterozygous (+/-) and homozygous (-/-) Ncx1lacZ mutant 9.0 dpc embryos viewed from the left side (a) and frontally (b). Note that Ncx1lacZ staining is present only within the heart and is stronger within the Ncx1-null embryo due to the presence of two copies of the reporter gene. In addition, the size of both embryos is very similar, looping has occurred normally, and the only phenotypic abnormality at this stage is the enlarged space (indicated by black arrow in panel a) between the primitive ventricle (V) and the sinus venous (SV). c) Whole-mount lacZ staining of normal heterozygous and Ncx1-null mutant 10.0 dpc embryos (both embryos had 29 somites) viewed from right side. Note that the mutant (-/-) embryo is severely growth retarded compared to the heterozygous embryo, but otherwise appears fairly normal. d) Transverse wax sections through the 10.0 dpc hearts (stained with hematoxylin/eosin) revealed trabecular formation and compaction within both the normal heterozygous and homozygous mutant embryos (indicated by black arrows). However, there does not appear to be any seeding of the endocardial cushions within the atrioventricular canal. e) Whole-mount lacZ staining of normal heterozygous and Ncx1-null mutant 11.0 dpc embryos (both embryos had 37 somites) viewed from the left side illustrating the left ventricle (LV) and atria (A). Note that the Ncx1-null embryo is severely growth retarded compared to the heterozygous embryo, but that the size of the Ncx1-null heart is comparable to that of the normal heterozygous heart. f, g) Frontal view by dark-ground illumination, of same embryos shown in panel e. Although the mutant heart (g) has correctly looped to the right-hand side, the future right ventricle/bulbus cordis region of the heart is severely underdeveloped (indicated by white arrowhead). h, i) Whole-mount nonradioactive in situ hybridization analysis of MLC2v mRNA expression within both wild-type (h) and Ncx1-null mutant (i) 10.5 dpc embryos. MLC2v expression is normally expressed within the ventricles and is absent from the atria within both embryos.

2. Normal heart morphogenesis (specification, looping, and chamber formation) occurs relatively normally within Ncx1-null embryos
Analysis of cardiac marker expression revealed that within 9.5 dpc embryos, the Ncx1-null hearts normally expressed a series of genes that are known to play an essential role in cardiac morphogenesis. MLC2v was normally expressed only in the Ncx1-null and wild-type ventricle and was absent from the atria (Fig. 1h , i ). dHAND expression was predominantly expressed within the future Ncx1-null right ventricle and eHAND expression was expressed mainly within the future Ncx1-null left ventricle (not shown), as expected.

3. Lack of Ncx1 results in an absence of spontaneous contractions
Since there was no discernible heartbeat in the Ncx1-nulls when compared to wild-type littermates, we set out to determine whether the upstream components of the E-C coupling process were affected in these mutants. Primitive embryonic heart tubes were loaded with the Ca²⁺ indicator fura-2/AM to measure intracellular Ca²⁺transients. If the sole defect in Ncx1-null embryos was that Ca²⁺ could not exit the cardiomyocyte, we would expect that the intracellular Ca²⁺ concentration would be elevated in the mutants and that there would be no normal phasic transients. Whereas rhythmic spontaneous Ca²⁺ transients were always present in wild-type and heterozygotes, such Ca²⁺ transients were never observed in 9.5 dpc Ncx1-null heart tubes. This result suggests that either the Ca²⁺ delivery mechanism or the contractile apparatus is defective.

To distinguish between these possibilities, we used electrical field stimulation in the ventricular region to artificially pace wild-type and Ncx1-null hearts. Ncx1-null heart tubes displayed relatively normal (albeit somewhat smaller) transient Ca²⁺ signals, suggesting that the Ca²⁺ delivery mechanism was fundamentally intact.

4. Ncx1 null embryos lack a functional contractile apparatus
As the upstream components of the E-C coupling process did not appear to be affected in these mutants, the organization of the downstream contractile apparatus was examined. Ultrastructural analysis revealed that the Ncx1-null cardiomyocytes have an almost complete absence of the normal parallel alignment of thick and thin filaments, myofibrillar disorganization, and lack of Z-lines when compared with normal littermates.

CONCLUSIONS

As both the ß-galactosidase reporter and endogenous Ncx1 mRNA (which is ubiquitously expressed within the adult animal) are expressed only within the embryonic heart prior to lethality (11.5 dpc), the Ncx1-null mutant essentially represents a heart-specific mutation of Ncx1. Surprisingly, this mouse mutant has a relatively normal developing embryonic heart (prior to in utero death) in the absence of a heartbeat, demonstrating that a heartbeat and/or circulation are not required for the early stages of heart morphogenesis and that the early embryonic heart develops autonomously.

Our data show that endogenous Ncx1 is expressed at least 8–12 h before the first irregular heartbeat ever occurs and that the Ncx1-null embryos have a completely disorganized contractile apparatus within 24 h following what would be the normal initiation of the heartbeat within mouse embryos. We cannot determine from our results whether the disorganized contractile apparatus is a primary defect that alone would prevent the embryonic heartbeat or whether the disorganized contractile apparatus is a secondary effect due to the lack of a heartbeat. However, our results do indicate a clear correlation between the lack of organization of contractile apparatus and lack of heartbeat, and further suggest that either the role of Ncx1 in myofibrillar organization is indirect and secondary to lack of heartbeat or that a hitherto unknown function of Ncx1 may be to initiate organization and/or stabilize the contractile apparatus integrity during early heart development.

The most striking finding was the unexpected rapid decay of electrically stimulated Ca²⁺ transients in our Ncx1-null embryos that lacked a heartbeat; Ncx1 should be the primary mechanism for Ca²⁺ removal in the early mouse embryo, since sarcoplasmic reticulum (if present) is thought to be minimal. Furthermore, even in the absence of Ncx1, overall basal Ca²⁺ levels were comparable to wild-type. This raises the intriguing possibility that, contrary to current understanding, Ca²⁺ extrusion through the surface membrane via Ncx1 may not be the primary mechanism for Ca²⁺ removal in the early mouse heart during E-C coupling. Thus, the embryonic and perinatal mouse may differ from other mammalian species in the relative maturity of SR Ca²⁺ transport function. Taken together, these results suggest the novel interpretation that up-regulation of the sarcolemmal Ca²⁺-ATPase, increased SR, or some other unknown mechanism is responsible for maintaining Ca²⁺ homeostasis within the embryonic hearts.

Given the presence of electrically stimulated Ca²⁺ transients (indicating functional voltage-gated Ca²⁺ channels) and the lack of spontaneous rhythmic activity in Ncx1-null embryo hearts, the lack of a heartbeat could be interpreted as an absence of the diastolic pacemaker potential. This would imply that inward current generated by the electrogenic Ncx1 in extruding Ca²⁺ during the relaxing phase of the preceding heartbeat leads to subsequent diastolic depolarization. Thus, Ncx1 may play an additional role in generating rhythmic cardiac activity during development.

View larger version (29K): [in this window] [in a new window]   Figure 2. Schematic diagram of the hypothesized functional role played by Ncx1 during embryonic excitation-contraction coupling. The embryonic heartbeat is shown as a highly simplified diagram of two different steps: relaxation and contraction. For a cardiomyocyte to contract, the intracellular Ca2+ levels need to rise rapidly, resulting in a reversible structural change within the contractile apparatus (represented in a highly simplified form composed of just actin and myosin). For relaxation to occur, intracellular Ca2+ levels have to be rapidly decreased, which reverses the structural change in the contractile apparatus, and the cell then relaxes. The targeted deletion of Ncx1 within mice suggests two novel findings: 1) Na+/Ca2+ exchange may not be the primary mechanism for removal of Ca2+ within embryonic hearts (as shown in green) and 2) Ncx1 may be involved in stabilization of contractile apparatus (as shown in blue).

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.00-0696fje ; to cite this article, use FASEB J. (March 12, 2001) 10.1096/fj.00-0696fje

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