Tyser, RCV; (2016) The role of functional calcium handling during the early stages of mouse heart development. Doctoral thesis , UCL (University College London).

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Abstract

During development the heart is the first organ to form and function in the embryo proper. Along with being fundamental for contraction, Ca2+ is also a key signalling molecule known to regulate cardiac genes, however, it is unclear how Ca2+-handling feeds-back onto the initiation of beating and whether this directly impacts on early embryonic heart development per se. The aim of this study was to investigate how initial contractions of the early mouse heart are established and what the downstream consequences of function are on cardiac differentiation and heart development. Using ex vivo Ca2+ imaging we found evidence of randomly distributed Ca2+ transients in the forming cardiac crescent, prior to contraction, suggesting early Ca2+ handling is essential for cardiomyocyte differentiation and subsequent heart development. To study the downstream effects of early Ca2+ we used a murine embryonic stem cell (mESC) model of cardiomyocyte differentiation which recapitulated heart development in vivo. Assessment of Ca2+ handling proteins indicated that the Na+-Ca2+ exchanger (NCX) was one of the earliest sarcolemmal transporters to be expressed, prior to the L-type Ca2+ channel (LTCC). Pharmacological inhibition of NCX revealed an essential early role in establishing and maintaining the first Ca2+ transients through to initiation of contraction; a role superseded by the LTCC as differentiation progressed. Upon NCX blockade cardiomyocyte differentiation was inhibited, coincident with the down-regulation of signature cardiac genes and calmodulin kinase signalling, which culminated in the failure of beating cardiomyocytes to form. This study points to a novel mechanism by which form and function are intricately linked such that, from the outset, Ca2+ acts to initiate contraction as well as regulate cardiac differentiation and the formation of the heart, adding an important layer onto our current understanding of mammalian cardiovascular development.

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