Conditional deletion of PKR1 in epicardial cells led to embryonic lethality and congenital heart defects, linked to miR-124-mediated EMT failure and myocardial immaturity.
The PKR1–miR-124–SNAI2 pathway is a critical mediator of epicardial–myocardial communication, offering a novel mechanistic framework and potential therapeutic target for congenital heart disease.
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Abstract Epicardial-to-mesenchymal transition (EMT) is essential for generating progenitor cells that shape cardiac development, but the molecular control of EMT and its paracrine effects on cardiomyocytes remain poorly elucidated. Here, we defined a novel PKR1–miR-124–SNAI2 signaling axis that orchestrates EMT and coordinates myocardial maturation. Conditional deletion of the prokineticin receptor (PKR1) in mice Tcf21+ epicardial cells caused embryonic lethality and congenital heart disease-like anomalies, including ventricular rupture, arrhythmia, myocardial fibrosis, and impaired contractility. Transcriptomic profiling revealed marked upregulation of miR-124, concurrent with deregulation of EMT genes and signatures of immature cardiomyocytes. Mechanistically, miR-124 directly targets the 3′ untranslated region of SNAI2, suppressing this key EMT regulator, resulting in failed EMT, apoptosis, and fibrosis in the epicardium. Functional rescue through miR-124 inhibition or PKR1 reintroduction restores SNAI2 expression, revives EMT, enhances cell survival, and promotes proper cardiomyocyte maturation. Paracrine effects were substantiated by conditioned media and ex vivo assays, demonstrating that epicardial-derived miR-124 suppressed cardiomyocyte contractility and cardiac maturity gene expression—thereby functionally linking epicardial disruption to myocardial immaturity. These findings establish miR-124 as a critical mediator of epicardial–myocardial communication with PKR1 as its upstream regulator. By integrating epicardial plasticity, myocardial maturation, and ECM homeostasis, our work reveals that targeting the PKR1–miR-124–SNAI2 pathway offers a novel mechanistic framework and potential therapeutic target for preventing or treating congenital heart disease.
Arora et al. (Mon,) reported a other. Conditional deletion of PKR1 in epicardial cells led to embryonic lethality and congenital heart defects, linked to miR-124-mediated EMT failure and myocardial immaturity.