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

引用

Journal of Molecular Cell Biology 2021年第1期13卷 41-58页

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 State Key Laboratory of Genetic Engineering School of Life SciencesZhong Shan HospitalFudan UniversityShanghai 200438China Shanghai Key Laboratory of Regulatory Biology Institute of Molecular MedicineEast China Normal University School of Life SciencesShanghai 200241China Department of Cell Biology Duke University Medical CenterDurhamNC 27710USA Department of Biochemistry and Molecular Biology Mayo ClinicRochesterMN 55905USA Department of Pathology and Laboratory Medicine McAllister Heart InstituteUniversity of North Carolina at Chapel HillChapel HillNC 27599USA Department of Developmental and Cell Biology Vanderbilt University School of MedicineNashvilleTN 37232USA T These authors share first authorship.

Heart regeneration occurs by dedifferentiation and proliferation of pre-existing cardiomyocytes(CMs).However,the signaling mechanisms by which injury induces CM renewal remain incompletely ***,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 *** 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 *** Wnt signaling is dampened upon injury,the cytoplasmic β-catenin is unexpectedly increased at disarrayed CM sarcomeres in myocardial wound *** 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 ***-specific induction of the phospho-mimeticβ-catenin(S675E)enhances CM dedifferentiation and sarcomere disassembly in response to ***,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

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