Abstract
Previous studies have demonstrated that inhibition of canonical Wnt signaling promotes zebrafish heart regeneration and that treatment of injured heart tissue with the Wnt activator 6-bromo-indirubin-3-oxime (BIO) can impede cardiomyocyte proliferation. However, the mechanism by which Wnt signaling regulates downstream gene expression following heart injury remains unknown. In this study, we have demonstrated that inhibition of injury-induced myocardial wnt2bb and jnk1/creb1/c-jun signaling impedes heart repair following apex resection. The expression of jnk1, creb1, and c-jun were inhibited in wnt2bb dominant negative (dn) mutant hearts and elevated in wnt2bb-overexpresssing hearts following ventricular amputation. The overexpression of creb1 sufficiently rescued the dn-wnt2bb-induced phenotype of reduced nkx2.5 expression and attenuated heart regeneration. In addition, wnt2bb/jnk1/c-jun/creb1 signaling was increased in Tg(hsp70l:dkk1) transgenic fish, whereas it was inhibited in Tg(hsp70l:wnt8) transgenic fish, indicating that canonical Wnt and non-canonical Wnt antagonize each other to regulate heart regeneration. Overall, the results of our study demonstrate that the wnt2bb-mediated jnk1/c-jun/creb1 non-canonical Wnt pathway regulates cardiomyocyte proliferation.
Highlights
Myocardial Infarction (MI) is a leading cause of morbidity and mortality in industrialized countries (Guo et al, 2016)
To confirm the RT-qPCR data, we performed in situ hybridization (ISH) analyses for creb1, c-jun, wnt2bb, and jnk1 and observed that the expression of creb1, jnk1 and c-jun mRNA increased in cardiomyocytes near the injury site at 7 dpa (Supplementary Figures S1A–F)
The immunostaining results showed that the expression of jnk1, c-jun, and creb1 protein was significantly increased in the CMs near the injury site (Figures 1B–G;K–M). c-Jun N-terminal kinases (JNKs) were originally identified as kinases that bind and phosphorylate c-jun on Ser-63 within its transcriptional activation domain
Summary
Myocardial Infarction (MI) is a leading cause of morbidity and mortality in industrialized countries (Guo et al, 2016). The massive lost cardiomyocytes (CMs) resulting from MI cannot be supplemented due to the low proliferation ability of adult human heart cells, and a lack of an adequate number of CMs causes chronic overload and subsequent dysfunction that leads to heart failure and death (Hajduk et al, 2013). There are two important phenotypes of CM dedifferentiation. The first is reactivation of embryonic cardiac genes, such as gata, hand, nkx2.5, and tbx in the myocardium surrounding the sites of injury (Lepilina et al, 2006; Kikuchi et al, 2010). The second phenotype of CM dedifferentiation requires the disassembly of sarcomeres (Jopling et al, 2010). The mechanism by which embryonic cardiac genes are reactivated
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