Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration  

作　　者：Xiangwen Peng Kaa Seng Lai Peilu She Junsu Kang Tingting Wang Guobao Li Yating Zhou jianjian Sun Daqing Jin Xiaolei Xu Lujian Liao Jiandong Liu Ethan Lee Kenneth D.Poss Tao P.Zhong 

机构地区：[1]State Key Laboratory of Genetic Engineering,School of Life Sciences,Zhong Shan Hospital,Fudan University,Shanghai 200438,China [2]Shanghai Key Laboratory of Regulatory Biology,Institute of Molecular Medicine,East China Normal University School of Life Sciences,Shanghai 200241,China [3]Department of Cell Biology,Duke University Medical Center,Durham,NC 27710,USA [4]Department of Biochemistry and Molecular Biology,Mayo Clinic,Rochester,MN 55905,USA [5]Department of Pathology and Laboratory Medicine,McAllister Heart Institute,University of North Carolina at Chapel Hill,Chapel Hill,NC 27599,USA [6]Department of Developmental and Cell Biology,Vanderbilt University School of Medicine,Nashville,TN 37232,USA T These authors share first authorship.

出　　处：《Journal of Molecular Cell Biology》2021年第1期41-58,共18页分子细胞生物学报（英文版）

基　　金：This research was supported by grants from the Ministry of Science and Technology of China(2018YFA0801004 and 2018YFA0800103);National Science Foundation of China(NSFC31530044 and NSFC31970780);We acknowledge Guozhen Wu for invaluable assistanee with fish care.We are grateful to Mark Mercola and members of TPZ laboratory for comments on the manuscript and helpful discussions.

摘　　要：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(Dkkl),Dkk3,secreted Frizzled-related protein 1(sFrpl),and sFrp2,in cardiac tissue adjacent to injury sites.Experimental blocking of Wnt activity via Dkkl 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-mimeticβ-catenin(S675E)enhances CM dedifferentiation and sarcomere disassembly in response to injury.Conversely,inactivation of Pak2 kinase activity reduces the Ser 675-phosphorylatedβ-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-βYatenin signaling enhances zebrafish heart regeneration by supporting CM dedifferentiation and proliferation.

关 键 词：heart regeneration Wnt signaling PAK2 kinase cardiomyocyte proliferation cardiomyocyte dedifferentiation ZEBRAFISH 

分 类 号：Q25[生物学—细胞生物学]