Calcium handling precedes cardiac differentiation to initiate the first heartbeat

Abstract

The mammalian heartbeat is thought to begin just prior to the linear heart tube stage of development. How the initial contractions are established and the downstream consequences of the earliest contractile function on cardiac differentiation and morphogenesis have not been described. Using high-resolution live imaging of mouse embryos, we observed randomly distributed spontaneous asynchronous Ca2+-oscillations (SACOs) in the forming cardiac crescent (stage E7.75) prior to overt beating. Nascent contraction initiated at around E8.0 and was associated with sarcomeric assembly and rapid Ca2+ transients, underpinned by sequential expression of the Na+-Ca2+ exchanger (NCX1) and L-type Ca2+ channel (LTCC). Pharmacological inhibition of NCX1 and LTCC revealed rapid development of Ca2+ handling in the early heart and an essential early role for NCX1 in establishing SACOs through to the initiation of beating. NCX1 blockade impacted on CaMKII signalling to down-regulate cardiac gene expression, leading to impaired differentiation and failed crescent maturation.DOI: http://dx.doi.org/10.7554/eLife.17113.001

Development of the human heart

“…At this stage differentiation proceeds quickly and the primitive cardiomyocytes start to spontaneously contract as a result of expression of (a) sarcomeric genes forming sarcomers, and (b) ion pumps and channels within the cell membrane allowing spontaneous depolarization. The contraction becomes polarized due to the electrical coupling of neighboring cells via gap junctions (Moorman et al, ; Moorman & Christoffels, ; Tyser et al, ).…”

“…The high proliferation rate of these progenitor cells is mediated through canonical Wnt/β-catenin signaling Ruiz-Villalba, Hoppler, & van den Hoff, 2016). Fluorescent labeling of these cells in chicken demonstrated their migration into the heart tube at both the venous and arterial poles (van den Berg et al, 2009). Mouse and human cardiac development display a similar course (de Boer et al, 2012b;Sizarov et al, 2011).…”

“…hardly any cardiomyocytes are supplement from a stem cell population (Jesty et al, 2012;van Berlo et al, 2014). A recent review extensively discusses this phase of heart development (Gunthel, Barnett, & Christoffels, 2018).…”

Sarcoplasmic reticulum Ca2+-induced Ca2+release regulates class IIa HDAC localization in mouse embryonic cardiomyocytes

“…At this stage, no sarcomeric banding or myocyte contraction can be observed (Tyser et al. ). Such an order of appearance, with Ca 2+ oscillations appearing prior to contractile elements, suggests that Ca 2+ signaling at very early stages of development may have a role in guiding cardiomyocyte differentiation.…”

Site and Mechanism of Action of Resin Acids on Voltage-Gated Ion Channels

“…The human genome encodes for ~140 voltage-gated ion channels (Yu and Catterall, 2004) that have different expression patterns in various cellular and subcellular compartments (Biel et al, 2009;Birnbaum et al, 2004;Catterall, 2000Catterall, , 2011Nerbonne and Kass, 2005;Vacher et al, 2008), and the expression also changes during development (Danielsson et al, 2013;Thompson et al, 2014;Tyser et al, 2016). The structure of voltage-gated ion channels is known from many experimental and structural studies that have been reviewed in detail previously Catterall et al, 2017;Yu and Catterall, 2004).…”