AUTHOR=Peng Xiangwen , Fan Shunyang , Tan Jing , Zeng Zhi , Su Meiling , Zhang Yuan , Yang Ming , Xia Luoxing , Fan Xuejiao , Cai Weibin , Tang Wai Ho 

TITLE=Wnt2bb Induces Cardiomyocyte Proliferation in Zebrafish Hearts via the jnk1/c-jun/creb1 Pathway

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=8

YEAR=2020

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.00323

DOI=10.3389/fcell.2020.00323

ISSN=2296-634X

ABSTRACT=<p>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 <italic>wnt2bb</italic> and <italic>jnk1/creb1/c-jun</italic> signaling impedes heart repair following apex resection. The expression of <italic>jnk1</italic>, <italic>creb1</italic>, and <italic>c-jun</italic> were inhibited in <italic>wnt2bb</italic> dominant negative (dn) mutant hearts and elevated in <italic>wnt2bb</italic>-overexpresssing hearts following ventricular amputation. The overexpression of <italic>creb1</italic> sufficiently rescued the <italic>dn-wnt2bb</italic>-induced phenotype of reduced <italic>nkx2.5</italic> expression and attenuated heart regeneration. In addition, <italic>wnt2bb/jnk1/c-jun/creb1</italic> signaling was increased in <italic>Tg(hsp70l:dkk1)</italic> transgenic fish, whereas it was inhibited in <italic>Tg(hsp70l:wnt8)</italic> 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 <italic>jnk1/c-jun/creb1</italic> non-canonical Wnt pathway regulates cardiomyocyte proliferation.</p>