Table 1 Cardiac genes/transcription factors/signaling pathways and their roles in cardiogenesis, proliferation/differentiation, and in CM development
Genes/TFs/Signaling pathways | Role in Cardiogenesis | Role in Proliferation/Differentiation | Possible Role in CM Development | Abbreviations |
|---|---|---|---|---|
Isl1 | Controls cardiomyocyte fate; highly expressed in multipotent CPCs [25,26,27,28,29] | Directs cardiac cell lineage and differentiation [30,31,32,33,34,35,36,37,38,39]. | Potential involvement in CM development; interacts with Nkx2–5 and Estrogen Receptor Alpha [40,41,42,43,44,45] | Isl1: Islet-1 CPCs: Cardiac Progenitor Cells CM: Cardiac Myxoma Nkx2–5: NK2 Homeobox 5 |
Brg1/Baf60 – Smarcd3 complex | Induces proliferation of CPCs. Differentiation becomes defective when there are defects in this complex [49,50,51,52,53,54,55]. | Baf60 complex may work with Wnt signaling pathway to promote tumorigenesis [47, 48]. | Brg1/Baf60 – Smarcd3 complex - Brahma-Related Gene 1/Brg1 Associated Factor 60, SMARCD3 Complex CPCs: Cardiac Progenitor Cells Wnt pathway - Wingless/Integrated Pathway | |
Nkx2–5 | Among the very first cardiac specific patterning genes [56, 57]. | Induces cardiac programming in CPCs. Enhances differentiation when interacting with Tbx5 and GATA4 [58,59,60,61,62,63,64,65,66,67,68]. | Upregulated expression in CM development. Potential contributor to the heterogeneity that exists in CM [69,70,71,72]. | Nkx2–5: NK2 Homeobox 5 CPCs: Cardiac Progenitor Cells Tbx5: T-Box 5 GATA4: GATA Binding Protein 4 CM: Cardiac Myxoma |
GATA4 | Important regulator of genes involved in cardiogenesis [73, 74]. | Plays a significant role in morphogenesis, survival and regulates differentiation [75,76,77,78,79]. | Decreased GATA4 expression changes cadiomyocytes into progenitor-like state [80, 81]. | GATA4: GATA Binding Protein |
Tbx5 | Increases the expression of other cardiogenic TFs [82,83,84,85,86]. | Enhances differentiation of CPCs into cardiomyocytes [87,88,89,90,91,92,93,94]. | Suppresses the expression of genes involved in non-cardiac cell types. Potential contributor to the heterogeniety in CM [95, 96]. | Tbx5: T-Box 5 CPCs: Cardiac Progenitor Cells CM: Cardiac Myxoma |
Mef2c | Contributes to the proliferation of CPCs and forms complexes with key cardiac TFs [97,98,99,100]. | Involved in cardiac morphogenesis. Works with the GATA4 and Tbx5 to enhance differentiation [101]. | In CM development, it may work with Wnt and Isl1 with resulting emergence of CPC-like state [102,103,104,105]. | Mef2c - Myocyte Enhancer Factor 2C GATA4: GATA Binding Protein 4 Tbx5: T-Box 5 Wnt pathway - Wingless/Integrated Pathway Isl1: Islet-1 CM: Cardiac Myxoma CPCs: Cardiac Progenitor Cells |
HAND1/2 | Enhances proliferation with Nkx2–5. On interaction with GATA4, it enhances the differentiation of cardiomyocytes [108, 109]. | It also acts as a tumor suppressor and is possibly downregulated in CM development [110] | HAND1/2: Heart- and Neural Crest-Derived Transcript 1/2 Nkx2–5: NK2 Homeobox 5 GATA4: GATA Binding Protein 4 CM: Cardiac Myxoma | |
MYOCD | Regulates the growth arrest of CPCs in cardiogenesis [111] | May contribute to the benign nature and rare occurrence of CM [111]. | MYOCD: Myocardin CPCs: Cardiac Progenitor Cells CM: Cardiac Myxoma | |
MSX2 | In cardiogenesis, MSX2 interacts with HAND1/2 and they regulate the gene expression of each other [114, 115] | Enhances the proliferation of CPCs [116] | In advanced CM, it may possibly contribute to the tumorigenesis by promoting progenitor-like state [116]. | MSX2: Msh Homeobox 2 HAND1/2: Heart- and Neural Crest-Derived Transcript 1/2 CPCs: Cardiac Progenitor Cells CM: Cardiac Myxoma |
HOPX | Expressed when CPCs become committed to cardiomyocyte fate [117]. | Enhances differentiation of cardiomyocytes. Also acts as a tumor suppressor [118, 119]. | Downregulation of HOPX may contribute to the CM development [117,118,119]. | HOPX: Homeodomain-Only Protein X CPCs: Cardiac Progenitor Cells CM: Cardiac Myxoma |
Wnt signaling pathway | Contributes to the dedifferentiation of cardiomyocytes into progenitor-like state in CM development [124, 125] | Wnt: Wingless/Integrated Pathway CPCs: Cardiac Progenitor Cells CM: Cardiac Myxoma | ||
FGF signaling pathway | Plays role in differentiating the pluripotent stem cells into CPCs [126,127,128,129] | Forms complexes with the key regulators of cell cycle to govern the differentiation and proliferation processes [130,131,132]. | Dysregulations and decline in the FGF signaling may cause reversal of cardiomyocytes towards progenitor-like state in CM development [133, 134]. | FGF: Fibroblast Growth Factor CPCs: Cardiac Progenitor Cells CM: Cardiac Myxoma |
BMPs | Downregulate the expression of the progenitor genes in CPCs [135,136,137]. | The downregulation of BMP expression may contribute to the CM development [136, 137]. | BMPs: Bone Morphogenetic Proteins CPCs: Cardiac Progenitor Cells CM: Cardiac Myxoma | |
Notch signaling pathway | Involved in the process of cardiac morphogenesis [140,141,142,143]. | Involved in the process of cardiomyocyte proliferation and differentiation [144,145,146]. | May work with Isl1 and Mef2c to contribute to the CM development [140, 141, 144]. | Notch: Notch Signaling Pathway Isl1: Islet-1 Mef2c: Myocyte Enhancer Factor 2C CM: Cardiac Myxoma |
PRKAR1A | Regulates the c-AMP protein kinase A signaling [147]. | Also acts as a tumor suppressor and contributes to the process of differentiation [148, 149]. | The mutation in PRKAR1A causes myxomas and carney complex [150, 151]. | PRKAR1A: Protein Kinase cAMP-Dependent Type I Alpha Regulatory Subunit c-AMP: Cyclic Adenosine Monophosphate PKA: Protein Kinase A |