35 Harnessing developmental cues for cardiomyocyte production 2 Figure 2. Heart size at selected stages of normal cardiac development. (A) Brightfield images capturing murine hyperplasia over embryonic day (E)9.5 (whole embryo; dashed white lines indicate the location of the heart), E12.5, E18.5 and postnatal day (P)2. (B) Brightfield images capturing murine hypertrophy from P13 to P60. (C) Immunofluorescent images showing pHH3+ cells in E12.5 and Ki67+ in LV cells of P2 and P13 hearts. pHH3 and Ki67 are proliferation markers and TnT is a cardiomyocyte marker. Ao, aorta; H, heart; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; TnT, troponin T; pHH3, phosphohistone H3. Figure is adapted from Buikema et al. (2013, 2020) and is available to view on Figshare alongside detailed Materials and Methods: 10.6084/ m9.figshare.23607306. Scale bars: ~1 mm (A,C); 5 mm (B). Interplay between Wnt, Hippo and IGF signaling during cardiomyocyte expansion The major regulator of cardiac size is the Hippo pathway. This pathway regulates growth and progenitor genes such as SOX2, SNAI2, CCND1, CDC20 and MYCL in cardiomyocytes via the MST1/2-SAV1-LATS1/2-MOB1-YAP/TAZ cascade (Heallen et al., 2011) (Figure 1). YAP, a central protein within the Hippo signaling pathway, is activated at CS10 (Singh et al., 2016). Genetic inhibition of Hippo signaling in the embryonic heart leads to a lack of organ
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