32 Chapter 2 the T-cell factor (TCF) and leukemia enhancer factor (LEF) transcription factors to activate Wnt target genes involved in cell proliferation such as axin 2 (AXIN2), cyclin D1 (CCND1) and lymphoid enhancer binding factor 1 (LEF1) (Cadigan and Waterman, 2012; Stamos and Weis, 2013) (Figure 1). Conversely, in the absence of Wnt ligands, a complex containing adenomatous polyposis coli (APC), casein kinase 1 (Ck1) and glycogen synthase kinase-3β (GSK-3β) mediates phosphorylation, ubiquitylation and, ultimately, degradation of β-catenin (Cadigan and Waterman, 2012; Stamos and Weis, 2013) (Figure 1). Conditional knockout studies for β-catenin in the SHF produce outflow tract abnormalities and impaired right ventricular development (Qyang et al., 2007; Lin et al., 2007). After specification and terminal differentiation of cardiac progenitors into cardiomyocytes, the developing heart predominantly increases its size and mass via the proliferation of differentiated cardiomyocytes (Günthel et al., 2018) (Table 1). In mice, between E8.0 and E11.0, cardiomyocyte numbers increase 100-fold from ∼700 to ∼70,000 (De Boer et al., 2012) (Figure 2A,C). During this massive growth phase, the size of the individual cardiomyocytes remains relatively constant. After E11.0, proliferation continues but at a slower rate, with cardiomyocyte numbers approaching 1,000,000 by E18.5 (de Boer et al., 2012). The ballooning ventricles exhibit the highest proliferation rates during this period (Moorman and Christoffels, 2003; Moorman et al., 2010). By contrast, the atrioventricular canal, outflow tract and inner curvature regions have lower proliferation rates and thereby preserve the slow contraction characteristics of the heart tube (De Jong et al., 1992). Proliferation rates may also vary within the same region depending on the developmental stage. Within the ventricles, proliferation rates are low during the formation of the trabecular network (Sedmera and Thompson, 2011). The trabeculae contribute to cardiac contractility, channel expression and energy metabolism, and start to develop at the luminal side of the myocardium by E9.5 or CS12 (Meyer et al., 2020; Günthel et al., 2018). Later in development, from CS12 until CS16, proliferation rates increase and the compacted ventricular chamber myocardium shows high expression of proliferative markers such as Ki67 and pHH3 (Buikema et al., 2013; Ye et al., 2015; Lin et al., 2015). These changes to ventricular proliferation rates are due to Wnt signaling. Canonical Wnt signaling is downregulated in the trabecular myocardium, which is consistent with the lower proliferation rates observed here (Buikema et al., 2013; Ye et al., 2015). By contrast, conditional knockout studies in mice have shown that epidermal growth factor receptor (EGFR) and Notch signaling are essential for trabecular development (Gassmann et al., 1995; Grego-Bessa et al., 2007). When proliferation rates in the ventricle increase, Wnt/β-catenin is essential for the exponential growth of the compacted ventricular myocardium; the increase in cardiomyocyte proliferation rates as you move from the inner trabeculae to outer compact myocardium corresponds with the graded activity of canonical Wnt signaling (Buikema et al., 2013; Ye et al., 2015). Consistent with this, β-catenin is mainly active in the compact myocardium, where it is expressed by the majority of proliferating cardiomyocytes (Buikema et al., 2013).
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