Calcium handling precedes cardiac differentiation to initiate the first heartbeat.

Richard Cv Tyser,Chiann-Mun Chen,Shankar Srinivas,Paul R Riley,Antonio Ma Miranda,Sean M Davidson

doi:10.7554/elife.17113

Richard Cv Tyser, Chiann-Mun Chen + Show 4 more

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https://doi.org/10.7554/elife.17113

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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.

Highlights

The heart is the first organ to form and function during mammalian embryonic development
It is commonly stated that initiation of contraction begins with the formation of the LHT (Bruneau, 2008), and whilst cardiac contractions have been reported just prior to the ‘linear heart tube’ stage (Navaratnam et al, 1986; Nishii and Shibata, 2006; Linask et al, 2001; Kumai et al, 2000; Porter and Rivkees, 2001), a precise study on the initiation of cardiac function has not been conducted
This can lead to ambiguities, as a ‘3-somite’ embryo may range from the cardiac crescent to early LHT stages

Summary

Introduction

The heart is the first organ to form and function during mammalian embryonic development. The CC subsequently expands and migrates to the midline whereupon, between E8.25 and E8.5, the two sides of the CC fuse and form the linear heart tube (LHT) (reviewed in Buckingham et al, 2005). Studies of heart development in model organisms have historically focused on the origin and spatial-temporal allocation of cardiac progenitors and cardiovascular lineage determination (Buckingham et al, 2005; Saga et al, 1996; Cai et al, 2003; Meilhac et al, 2004; Wu et al, 2006; Moretti et al, 2006; Evans et al, 2010; Devine et al, 2014). Given the forming heart contracts from an early stage, this raises the important

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