34 Chapter 2 Table 1: Signaling pathways and regulators in heart development. Early embryonic development Intermediate embryonic development Late embryonic development Early postnatal stages Adolescence Adulthood Event(s) Cardiac looping, EMT, proliferation Cardiac expansion, chamber formation Septation, valvulation, conduction system formation Maturation, mitochondrial fatty acid oxidation Bi-nucleation of cardiomyocytes Hypotrophy Pathways involved during heart development Hippo, Notch, BMP, SMAD, TGF, FGF, Wnt, EGFR1 Hippo, Wnt, Notch, BMP, FGF, IGF, RA TNFα, NF-κB, IL6, Notch/ HEY2 T3, cTnI, VHL/ HIF1, FAO, PGC1α PPARA, Esrra, Mef2, Myod, SIRT1, E2f/Rb T3, insulin, HOPX, VEGFB, IGF1, AMPK Mouse development Developmental Stage E9.5 E12.5 E18.5 P2 P13 P60 Heart size (mm) 0.2 0.8 1.1 1.8 5 8 Number of CMs <10.000 (Alkass, 2015) ~70,000 (Alkass, 2015) ~1,000,000 (Alkass, 2015) ~1,700,000 (Alkass, 2015) ~2,500,000 (Alkass, 2015) ~2,500,000 (Alkass, 2015) Proliferation (% ki67+) N/A 45 (Lin, 2007) N/A 28-37 (Alkass, 2015, Huang, 2018) 5 (Alkass, 2015) 0.01-1 (Castellan, 2020, Huang, 2018) Proliferation (% PH3+) N/A 2 (Lin, 2007) N/A 10 (Gan, 2015) 2 (Gan, 2015) N/A Human development Developmental stage CS3-4 CS4 CS6-7 1 month 20 years >40 years Heart size (mm) 0.003 (Günthel, 2018) 2 (Günthel, 2018) 10 (Dhanantwari, 2009) ~40 (Faber, 2021) ~110 (Mohammadi, 2016) ~120 (Mohammadi 2016) Number of CMs N/A N/A N/A 90,000,000 (Mollova, 2013) 3,200,000,000- 3,700,000,000 (Bergmann, 2015, Mollova, 2013) 3,200,000,000 (Bergmann, 2015) Proliferation (% ki67+) N/A N/A N/A 0.5 (Ye, 2016) 0.04 (Mollova, 2013) 0.001 (Mollova, 2013) Proliferation (% PH3+) N/A N/A N/A 0.01 (Mollova, 2013) 0.005 (Mollova, 2013) 0 (Mollova, 2013) MPK, AMP-activated protein kinase; BMP, bone morphogenetic protein; CS, Carnegie stage; cTnI, cardiac troponin I; E, embryonic day; EMT, epithelial-to-mesenchymal transition; EGFR1, epidermal growth factor receptor 1; Esrra, estrogen-related receptor alpha; FAO, fatty acid oxidation; FGF, fibroblast growth factor; HEY2, Hes related family BHLH transcription factor with YRPW motif 2; HOPX, homeodomain-only protein homeobox; IGF, insulin-like growth factor; IL6, interleukin 6; Mef2, MADS box transcription enhancer factor 2; Myod, myoblast determination protein 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; P, postnatal day; PGC1α, PPARγ coactivator 1 α; pHH3, phosphohistone H3; PPARA, peroxisome proliferator-activated receptor; RA, retinoic acid; Rb, retinoblastoma; SIRT1, sirtuin 1; SMAD, mothers against decapentaplegic; T3, thyroid hormone; TGF, transforming growth factor; TNFα, tumor necrosis factor α; VEGFB, vascular endothelial growth factor; VHL/HIF1, von Hippel-Lindau tumor suppressor protein/hypoxia-inducible factor-1.
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