BMP and Notch Signaling Pathways differentially regulate Cardiomyocyte Proliferation during Ventricle Regeneration

Abstract

Adult mammalian hearts show limited capacity to proliferate after injury, while zebrafish are capable to completely regenerate injured hearts through the proliferation of spared cardiomyocytes. BMP and Notch signaling pathways have been implicated in cardiomyocyte proliferation during zebrafish heart regeneration. However, the molecular mechanism underneath this process as well as the interaction between these two pathways remains to be further explored. In this study we showed BMP signaling was activated after ventricle ablation and acted epistatic downstream of Notch signaling. Inhibition of both signaling pathways differentially influenced ventricle regeneration and cardiomyocyte proliferation, as revealed by time-lapse analysis using a cardiomyocyte-specific FUCCI (fluorescent ubiquitylation-based cell cycle indicator) system. Further experiments revealed that inhibition of BMP and Notch signaling led to cell-cycle arrest at different phases. Overall, our results shed light on the interaction between BMP and Notch signaling pathways and their functions in cardiomyocyte proliferation during cardiac regeneration.

Direct BMP signaling to chordoblasts is required for the initiation of segmented notochord sheath mineralization in zebrafish vertebral column development

“…Further research is needed to dissect the functional and genetic correlation between BMP and Notch. In other contexts, ranging from vein formation in Drosophila wings ( 48 ) to zebrafish heart regeneration ( 49 ), Notch signaling has been reported to act upstream of BMP/Dpp signaling. However, as in the case of BMP and RA described here, corresponding epistasis analyses have to be taken with caution, as one factor being epistatic to another does not necessarily mean that it acts downstream, but could rather be involved in an earlier step of the biological process.…”

Ercc2/Xpd deficiency results in failure of digestive organ growth in zebrafish with elevated nucleolar stress

“…WISH was performed using Digoxigenin-labeled RNA antisense probes ( Li et al., 2020 ; Wang et al., 2021 ). Briefly, zebrafish embryos were fixed in 4% paraformaldehyde (PFA) overnight at 4°C.…”

“…Whole-mount in situ hybridization WISH was performed using Digoxigenin-labeled RNA antisense probes (Li et al, 2020;Wang et al, 2021). Briefly, zebrafish embryos were fixed in 4% paraformaldehyde (PFA) overnight at 4 C. After rinsed with PBS, embryos were digested with 10 mg/ml proteinase K in PBST (0.1% Tween 20 in PBS) and re-fixed with 4% PFA for 20 min, followed by pre-hybridization in hybridization buffer for 3 to 5 h at 68 C, then incubated overnight with probes (1 ng/ml) diluted in hybridization buffer at 68 C. Detection was performed using 1:4000 dilution of anti-Digoxigenin-AP antibody and visualized by NBT/BCIP substrate reaction.…”

A review on regulation of DNA methylation during post-myocardial infarction

“…Numerous studies have demonstrated the involvement of the Notch signaling pathway in processes relevant to the regulation of cardiomyocyte proliferation during heart development ( Pedrazzini, 2007 ; Niessen and Karsan, 2008 ; de la Pompa and Epstein, 2012 ; MacGrogan et al, 2018 ; Wang et al, 2021 ). In particular, Notch1 is highly expressed in immature proliferating cardiomyocytes during the early neonatal period to protect them from apoptosis ( Collesi et al, 2008 ).…”