PUBLICATION
Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration
- Authors
- Peng, X., Lai, K.S., She, P., Kang, J., Wang, T., Li, G., Zhou, Y., Sun, J., Jin, D., Xu, X., Liao, L., Liu, J., Lee, E., Poss, K.D., Zhong, T.P.
- ID
- ZDB-PUB-210216-5
- Date
- 2020
- Source
- Journal of molecular cell biology 13(1): 41-58 (Journal)
- Registered Authors
- Liu, Jiandong, Poss, Kenneth D., Xu, Xiaolei, Zhong, Tao P.
- Keywords
- PAK2 kinase, Wnt signaling, cardiomyocyte dedifferentiation, cardiomyocyte proliferation, heart regeneration, zebrafish
- MeSH Terms
-
- Animals
- Cell Proliferation
- Disease Models, Animal
- Heart Injuries/pathology*
- Humans
- Intercellular Signaling Peptides and Proteins/metabolism
- Myocytes, Cardiac/pathology*
- Protein Serine-Threonine Kinases/metabolism
- Regeneration/physiology*
- Sarcomeres/pathology
- Wnt Signaling Pathway/physiology*
- Zebrafish
- Zebrafish Proteins/metabolism
- beta Catenin/metabolism
- PubMed
- 33582796 Full text @ J. Mol. Cell Biol.
Citation
Peng, X., Lai, K.S., She, P., Kang, J., Wang, T., Li, G., Zhou, Y., Sun, J., Jin, D., Xu, X., Liao, L., Liu, J., Lee, E., Poss, K.D., Zhong, T.P. (2020) Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration. Journal of molecular cell biology. 13(1):41-58.
Abstract
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.
Errata / Notes
This article is corrected by ZDB-PUB-220202-5.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping