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Cardiogenesis

Summary

Organism

Homo sapiens (human)

Reactome

R-HSA-9733709

PubChem

R-HSA-9733709

Description

Gradients of Bone Morphogenetic Protein (BMP), Wingless-related integration site (WNT), and NODAL promote the formation of cardiac progenitors anteriolateral to the primitive streak during gastrulation (reviewed in Munoz-Chapuli and Perez-Pomares 2010, Cui et al. 2018, Prummel et al. 2020, Witman et al. 2019, Miyamoto e al. 2021). Eomesodermin (EOMES) and TBXT (T, Brachyury) expressed in the cardiac mesoderm activate expression of MESP1, a master regulator of cardiogenesis and the first observed marker of cardiac progenitors. MESP1-expressing cells migrate anteriorly towards the midline to form the cardiac crescent posterior to the head folds at about 2 weeks of gestation in humans (E7.5 in mice).

Within the cardiac crescent, two populations of cells can be identified based on gene expression and timing of contribution to the developing heart: the first heart field (FHF) forms the initial heart tube and contributes to the systemic ventricle (the left ventricle in crocodilians, birds, and mammals), the septum, and, to a lesser extent, the atria; the second heart field (SHF) extends the poles of the heart and contributes to the atria, the outflow tract, the septum, and the right ventricle, which is responsible for pulmonary circulation and distinguishes crocodilians, birds, and mammals (reviewed in Meilhac and Buckingham 2018).

At about 3 weeks gestation in humans (E8 in mice), FHF cells migrate axially to the midline and fuse to form the heart tube. Elongation of the heart tube leads to rightward looping and eventual formation of atria and ventricles (reviewed in Desgrange et al. 2018). FHF cells do not proliferate as much as SHF cells and mostly differentiate into cardiomyocytes due to the actions of myocardial differentiation factors such as NKX2-5, GATA4, TBX5, and HAND1. SHF cells are initially located in the posterior region of the cardiac crescent then, during formation of the heart tube, become located at the arterial and venous poles of the heart tube. SHF cells proliferate more than FHF cells and can differentiate to form cardiomyocytes, endothelial cells, smooth muscle cells, and fibroblasts. A reservoir of SHF progenitors located at the core of the pharyngeal mesoderm continuously contributes to the developing heart. Proliferating SHF cells express FGF8 and FGF10 driven by ISL1 and TBX1.

Cardiac progenitors are regulated by a distinct set of transcription factors and mutations in these factors and other factors involved in gene expression are responsible for congenital heart defects (reviewed in Diab et al. 2021, Houyel and Meilhac 2021, Kodo et al. 2021, Miyamoto et al. 2021, Lescroart and Zaffran 2022, Wang et al. 2022). Additionally, combinations of these transcription factors are now being used to reprogram fibroblasts and other cell types into cardiomyocytes for repairing damaged hearts (reviewed in Adams et al. 2021, Garry et al. 2021, Kim et al. 2022, Thomas et al. 2022, Zhu et al. 2022). TBXT (T, Brachyury) is expressed early in developing mesoderm and is activated by WNT signaling, which maintains proliferation and is subsequently downregulated during differentiation. Activation of MESP1 expression by TBXT and EOMES occurs early in gastrulation. MESP1 is expressed in both the FHF and the SHF. MESP1, in turn, directly activates two key regulators of cardiac development: GATA4 and NKX2-5 (NKX2.5, the ortholog of Tinman in Drosophila). Bone Morphogenetic Protein (BMP) signaling originating from BMPs secreted by underlying endoderm also enhances expression of GATA4 and NKX2-5, apparently through binding of SMAD proteins to the promoters of GATA4 and NKX2-5. GATA4 and NKX2-5 proteins, in turn, regulate each other's expression and directly interact to regulate downstream target genes. NKX2-5 directly activates GATA6 throughout the cardiac mesoderm.

The FHF is characterized by expression of TBX5 and HCN4; the SHF is characterized by transient expression of TBX1, ISL1, FGF8, FGF10, and SIX2. In the FHF, NKX2-5 binds the promoter of the TBX5 gene and activates transcription. TBX5, in turn, directly activates expression of SRF. TBX5 protein interacts directly with NKX2-5 and GATA4 proteins to activate further downstream targets. Sonic hedgehog (SHH) from the pharyngeal endoderm and WNT signaling maintain proliferation of SHF cells, In the SHF, TBX1, GATA4 and LEF1:CTNN1 (LEF1:Beta-catenin from Wnt signaling) directly activate ISL1, characteristic of SHF cells, and ISL1 then activates expression of HAND2 (dHAND), also characteristic of SHF cells.

Click on a node on the pathway to see its details. Glycoproteins are marked with a glycoprotein icon in their name.

SPV: a JavaScript Signaling Pathway Visualizer, Bioinformatics, 2018

Displaying entries **1 - 10** of 13 in total

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UniProt ID	Protein Name	Gene Symbol	Pathway Viewer
O15178	T-box transcription factor T	T TBXT	view
O95936	Eomesodermin homolog	EOMES TBR2	view
P11831	Serum response factor	SRF	view
P35222	Catenin beta-1	CTNNB CTNNB1 OK/SW-cl.35 PRO2286	view
P43694	Transcription factor GATA-4	GATA4	view
P61964	WD repeat-containing protein 5	BIG3 WDR5	view
P98177	Forkhead box protein O4	AFX AFX1 FOXO4 MLLT7	view
Q06413	Myocyte-specific enhancer factor 2C	MEF2C	view
Q13485	SMAD family member 4	DPC4 MADH4 SMAD4	view
Q86U70	LIM domain-binding protein 1	CLIM2 LDB1	view

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