The Na+–Ca2+ Exchanger Is Essential for Embryonic Heart Development in Mice

Abstract

The cardiac Na+ -Ca2+ exchanger 1 (NCX1) is thought to be the major calcium extrusion mechanism and to play an important role in the regulation of intracellular calcium in the heart. The Na+ -Ca2+ exchanger is particularly abundant in the heart, although it is found in a variety of other tissues. To investigate the role of NCX1, we have generated NCX1-deficient mice. Mice heterozygous for the NCX1 mutation showed no discernable phenotype, grew normally, and were fertile; however, no viable homozygote was observed among 175 offspring obtained from intercrosses of heterozygotes. All the homozygous mutant mice died in utero before E10.5. Morphological analysis indicated that homozygotes of NCX1 mutation at E9.5 died with an underdeveloped heart with a dilated pericardium. Microscopic analysis of these embryos showed myocardial cell loss due to apoptosis. The apoptosis was first observed in E8.5 mutant heart. Areas outside the heart appeared normal in the mutant embryos at E8.5. In contrast, at E9.0, various regions of mutant embryos showed extensive cell loss. These results suggest that mutant embryos die owing to cardiac abnormalities caused by apoptotic cell loss, indicating that NCX1 is essential for normal development of the heart.

Molecular Regulation of Cardiomyocyte Differentiation

“…4 The heart’s ability to generate blood flow at this stage is critical to the continuation of cardiogenesis and to other processes in embryogenesis that respond to hemodynamic signals. 5–9 The process of rightward looping occurs in conjunction with the addition of the SHF cells to both poles of the linear heart tube. Concurrently, the developing atria migrate and become cranially positioned relative to the ventricles.…”

Development and function of tissue resident macrophages in mice

“…Brain microglia is labeled more efficiently than other tissue resident macrophages when tamoxifen is applied at E7.5 in Runx1 MER-iCre-MER , Tie2 MER-iCre-MER and Kit MER-iCre-MER (73,80,92). These findings, together with the comparison of the labeling efficiency over time of microglia and macrophages in other tissues after a single tamoxifen pulse (62,65,70), has led some authors to hypothesize that they could originate from different YS progenitors.…”

“…This hypothesis is supported by the analysis of blood-circulation-deficient animals like the cardiac Na + -Ca 2+ exchanger ( Ncx1) knockout mice. Ncx1 -deficient animals die in utero at 9.5 dpc due to heart failure and lack of blood circulation (80,81) and they show an accumulation of macrophages in the YS, but a decrease of microglial cells in the developing neuroectoderm (62). Similarly, YS-EMPs are not detected in the fetal liver in Ncx1- deficient embryos, but increase massively in the YS (75).…”

Catecholamines and development of cardiac pacemaking: An intrinsically intimate relationship

“…6 is the sodium-calcium exchanger, NCX1, which is expressed early in cardiac development [58] where it is thought to play a critical role extruding Ca 2+ and providing an inward current in primitive pacemaking cells [59]. Indeed, genetically-altered mice with NCX1 deficiency die early in development (∼ E9) with no detectable heart beats [60][61][62]. Although catecholamines do not appear to influence mammalian NCX1 activity directly, [63] they may nevertheless affect NCX1 by stimulating expression of the NCX1 gene through α 1 -adrenergic receptors [64,65].…”