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

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...

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Autores principales: Peng, Xiangwen, Lai, Kaa Seng, She, Peilu, Kang, Junsu, Wang, Tingting, Li, Guobao, Zhou, Yating, Sun, Jianjian, Jin, Daqing, Xu, Xiaolei, Liao, Lujian, Liu, Jiandong, Lee, Ethan, Poss, Kenneth D, Zhong, Tao P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035995/
https://www.ncbi.nlm.nih.gov/pubmed/33582796
http://dx.doi.org/10.1093/jmcb/mjaa046
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author Peng, Xiangwen
Lai, Kaa Seng
She, Peilu
Kang, Junsu
Wang, Tingting
Li, Guobao
Zhou, Yating
Sun, Jianjian
Jin, Daqing
Xu, Xiaolei
Liao, Lujian
Liu, Jiandong
Lee, Ethan
Poss, Kenneth D
Zhong, Tao P
author_facet Peng, Xiangwen
Lai, Kaa Seng
She, Peilu
Kang, Junsu
Wang, Tingting
Li, Guobao
Zhou, Yating
Sun, Jianjian
Jin, Daqing
Xu, Xiaolei
Liao, Lujian
Liu, Jiandong
Lee, Ethan
Poss, Kenneth D
Zhong, Tao P
author_sort Peng, Xiangwen
collection PubMed
description 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.
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spelling pubmed-80359952021-04-14 Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration Peng, Xiangwen Lai, Kaa Seng She, Peilu Kang, Junsu Wang, Tingting Li, Guobao Zhou, Yating Sun, Jianjian Jin, Daqing Xu, Xiaolei Liao, Lujian Liu, Jiandong Lee, Ethan Poss, Kenneth D Zhong, Tao P J Mol Cell Biol Articles 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. Oxford University Press 2020-09-16 /pmc/articles/PMC8035995/ /pubmed/33582796 http://dx.doi.org/10.1093/jmcb/mjaa046 Text en © The Author(s) (2020). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Articles
Peng, Xiangwen
Lai, Kaa Seng
She, Peilu
Kang, Junsu
Wang, Tingting
Li, Guobao
Zhou, Yating
Sun, Jianjian
Jin, Daqing
Xu, Xiaolei
Liao, Lujian
Liu, Jiandong
Lee, Ethan
Poss, Kenneth D
Zhong, Tao P
Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration
title Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration
title_full Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration
title_fullStr Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration
title_full_unstemmed Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration
title_short Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration
title_sort induction of wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035995/
https://www.ncbi.nlm.nih.gov/pubmed/33582796
http://dx.doi.org/10.1093/jmcb/mjaa046
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