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Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration
Xiangwen Peng1,2,† , Kaa Seng Lai1,2,† , Peilu She2 , Junsu Kang3 , Tingting Wang2 , Guobao Li1 , Yating Zhou2 , Jianjian Sun2 , Daqing Jin2 , Xiaolei Xu4 , Lujian Liao2 , Jiandong Liu5 , Ethan Lee6 , Kenneth D. Poss3 , Tao P. Zhong2,*
1State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhong Shan Hospital, Fudan University, Shanghai 200438, China
2Shanghai Key Laboratory of Regulatory Biology, Institute of Molecular Medicine, East China Normal University School of Life Sciences, Shanghai 200241, China
3Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
4Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
5Department of Pathology and Laboratory Medicine, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
6Department of Developmental and Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
These authors share first authorship.
*Correspondence to:Tao P. Zhong ,
J Mol Cell Biol, Volume 13, Issue 1, January 2021, Pages 41-58
Keyword: heart regeneration, Wnt signaling, PAK2 kinase, cardiomyocyte proliferation, cardiomyocyte dedifferentiation, zebrafish

Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). However, the signaling mechanisms by which injury induces CM renewal remain incompletely understood. Here, we find that cardiac injury in zebrafish induces expression of the secreted Wnt inhibitors, including Dickkopf 1 (Dkk1), Dkk3, secreted Frizzled-related protein 1 (sFrp1), and sFrp2, in cardiac tissue adjacent to injury sites. Experimental blocking of Wnt activity via Dkk1 overexpression enhances CM proliferation and heart regeneration, whereas ectopic activation of Wnt8 signaling blunts injury-induced CM dedifferentiation and proliferation. Although Wnt signaling is dampened upon injury, the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound edges. Our analyses indicated that p21-activated kinase 2 (Pak2) is induced at regenerating CMs, where it phosphorylates cytoplasmic β-catenin at Ser 675 and increases its stability at disassembled sarcomeres. Myocardial-specific induction of the phospho-mimetic β-catenin (S675E) enhances CM dedifferentiation and sarcomere disassembly in response to injury. Conversely, inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylated β-catenin (pS675-β-catenin) and attenuates CM sarcomere disorganization and dedifferentiation. Taken together, these findings demonstrate that coordination of Wnt signaling inhibition and Pak2/pS675-β-catenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.